Chem Biol Drug Des - 2022 - Kizhakkedath Ratheesh - Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in

Received: 23 March 2022
| Revised: 11 July 2022

| Accepted: 17 July 2022
DOI: 10.1111/cbdd.14124
REVIEW
Pyrimidine derivatives as EGFR tyrosine kinase inhibitors

in non-small-cell lung cancer: A comprehensive review
Anandu Kizhakkedath Ratheesh | Ajay Pottankottu Jayan |

Aneesh Thankappan Presanna | Saiprabha Vijayakumar Nirmala
Amrita School of Pharmacy, Amrita

Vishwa Vidyapeetham, Kochi, India Abstract
EGFR-positive non-small-cell lung cancer (NSCLC) due to primary mutation
Correspondence
(EGFR DEL19 & L858R) has been recognized as a crucial mediator of tumor
Aneesh T. P and Saiprabha V. N,
Department of Pharmaceutical progression. This led to the development and approval of EGFR tyrosine kinase
Chemistry and Analysis, Amrita inhibitors, which addresses EGFR-mediated NSCLC but fail to show potency
School of Pharmacy, Amrita Vishwa
Vidyapeetham, AIMS Health Sciences
after initial months of therapy due to acquired resistance (EGFR T790M, EGFR
Campus, Kochi, Kerala, India. C797S). Extensive research allowed identification of drugs for EGFR-positive
Emails: aneeshtp@aims.amrita.edu; NSCLC, wherein the majority of compounds have a pyrimidine substructure of-
aneesh21atp@gmail.com (ATP);
saiprabhavn@pharmacy.aims.amrita. fering marked therapeutic benefits compared with chemotherapy. This current
edu; saiprabhavn@gmail.com (SVN) review outlines the diverse pyrimidine derivatives with amino-linked and fused
pyrimidine scaffolds such as furo-pyrimidine, pyrimido-pyrimidine, thieno-
Funding information
Amrita Vishwa Vidyapeetham pyrimidine, highlighting pyrimidine EGFR TK inhibitors reported in research
emphasizing structural aspects, design approaches, inhibition potential, selectiv-
ity profile toward mutant EGFR conveyed through biological evaluation studies.
Furthermore, mentioning the in-silico interaction profile of synthesized com-
pounds for evaluating the binding affinity with key amino acids. The epilogue of
review focuses on the recent research that drives forward to aid in the discovery
and development of substituted amino and fused scaffolds of pyrimidine that can
counteract the mutations and effectively manage EGFR-positive NSCLC.
KEYWORDS
NSCLC, EGFR TK inhibitors, pyrimidine, EGFR mutations, EGFR, EGFR-positive NSCLC
1 | I N T RO DU CT ION after moderate progression of cancer. Imaging and tissue

sampling techniques were employed to screen whether
Cancer has been the single most lethal disease diagnosed the person has lung cancer. Lung cancer is classified into
worldwide annually. It is caused by the rapid division of two types based on cell size: (I) non-small-cell lung cancer
abnormal cells uncontrollably, producing tumors (Ferlay (NSCLC) and (II) small-cell lung cancer (SCLC). NSCLC is
et al., 2018). Reports estimate about 19.3 million cases and seen in about 80%–85% of those, which were further sub-
10 million deaths globally in 2018. Currently, lung can- categorized as (i) adenocarcinomas, (ii) squamous cell car-
cer is ranked as the second-most common cancer in both cinomas, and (iii) large cell carcinomas (Horn et al., 2013).
genders, with 2 million newly diagnosed and 1.8 million SCLC is found in approximately 10%–15% of cases
deaths as of 2020 (Cancer, 2022). Lung cancer is difficult (Govindan et al., 2006). Treatment options for NSCLC in-
to diagnose in the early stages as symptoms start to show clude surgery to remove the tumor, chemotherapy to slow
Chem Biol Drug Des. 2022;100:599–621. wileyonlinelibrary.com/journal/cbdd © 2022 John Wiley & Sons Ltd. | 599
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17470285, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cbdd.14124 by Jiangsu University, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
600 KIZHAKKEDATH RATHEESH et al.
tumor cell growth, radiation to kill tumor cells, targeted and current tertiary resistance C797S expedite the need of
therapy to inhibit key genes and proteins in cancer cells, fourth-generation EGFR TKIs (Nan et al., 2017; Thomas
and immunotherapy to destroy tumor cells in combina- et al., 2019; Figure 1). Accounting that the majority of
tion based on the severity of the disease condition (Lung the EGFR tyrosine kinase inhibitors have a pyrimidine
Cancer, 2022). Target therapy allows specific treatment
of NSCLC by targeting the signaling pathways leading to
the progression of tumor cells, providing better outcomes
and lower toxicity compared with other treatment op-
tions. Various targeted therapies include drugs targeting
EGFR, BRAF, ALK, ROS, MET, RET, and NTRK (Joshua
et al., 2018; Minuti et al., 2013; Sreelakshmi et al., 2019).
Out of these targets, EGFR is held as an encouraging tar-
get because reports show more than 50% of people have
positive signs of mutation of EGFR in NSCLC (Parambi
et al., 2020). EGFR is a transmembrane protein belong-
ing to the tyrosine kinase receptor family, modulating the
growth signals in cells by action on various prime func-
tions involving growth, proliferation, division, and sepa-
ration (Da Cunha Santos et al., 2011). The EGFR receptor
gets activated by ligand interaction with the extracellular
binding site, leading to dimerization, which allows for
intracellular domain site phosphorylation and a signal-
ing cascade that results in cell proliferation and apoptosis
inhibition (Dacic et al., 2006). It has been observed that
the upregulation of EGFR signals in NSCLC potentially F I G U R E 1 EGFR protein structure (PDB ID – 6LUD) with
allows the advancement of cancer cells caused by apop- triple mutant L858R/T790M/C797S
tosis inhibition and the elevated spread of tumors due
to mutations in EGFR protein such as 19del and L858R
(Antonicelli et al., 2013). The Adenine pocket, hydrophilic
ribose pocket, hydrophobic area I, hydrophobic region II,
and phosphate binding region make up the ATP binding
site of EGFR-TK. Wherein, EGFR TKIs connect to this
binding area with the following key interaction based on
SAR and pharmacophoric features. (a) Central heteroaro-
matic system mainly pyrimidines analogs that contain at
least one H-bond acceptor that occupies the adenine bind-
ing area known as hinge segment forming hydrogen bond-
ing interactions with the key amino acid residues such as
Thr854, Thr790, and Met793. (b) The hydrophobic head
in the terminal end allows for interaction with the hydro-
phobic region I. This hydrophobic head in most cases has
a phenyl ring with separate additional hydrophobic sub-
stitutions. (c) NH spacer acts as a linker connecting the
adenine binding region and the hydrophobic region. (d)
The hydrophobic tail is positioned toward hydrophobic
region II with direct contract with the core ring system
(Traxler & Furet, 1999; Zhang et al., 2009; Figures 2 and
3). This led to the development of first-generation EGFR
tyrosine kinase inhibitors such as erlotinib and gefitinib F I G U R E 2 Binding interaction profile of first-generation EGFR
to target these specific mutations but acquired resistance TKIs Erlotinib indicating one hydrogen bond with Met 769 (green
takes place in months due to further mutation in EGFR color), Carbon-hydrogen bond with Leu764, Met 769, Gln767, Thr
like T790M allowing further expansion toward second 830, and hydrophobic interactions (pale green color) with Ala719,
and third generations of EFGR tyrosine kinase inhibitors Lys721, Val702, Leu 694, Gln767, and Lue820 (purple color)
|
KIZHAKKEDATH RATHEESH et al. 601
nucleus (Table 1; Figure 4) responsible for the binding and potent inhibition in kinase assay and cellular assay with
therapeutic action in NSCLC treatment. The pyrimidine IC50 of 4.10 nM (EGFRL858R/T790M) and 10 nM (H1975 cell
ring is a six-membered heterocyclic compound having two line) respectively (Table 2). H1975 cells (human NSCLC
nitrogen atoms in 1, 3 positions of the ring. Substituted cell line with the EGFR-L858R/T790M mutation) were
and annulated pyrimidine rings have shown potent phar- used for in vivo experiments to compare the antitumor ef-
macotherapeutic actions in antibacterial properties such fects of several compounds with that of reference,
as Iclaprim and Trimethoprim (Abd El-Aleam et al., 2020; AZD9291. The findings demonstrated that, as compared
Fang et al., 2019), antifungal (Blokhina et al., 2021; Wu with vehicle-treated groups, the mean final tumor vol-
et al., 2019) such as Hexetidine and Flucytosine, anti- umes for all drug-treated groups were significantly lower.
inflammatories such as Epirizole and Afloqualone A1 with doses of 10 and 20 mg/kg/day, the tumor growth
(Mohamed et al., 2010; Sondhi et al., 2005), antiviral such inhibition (TGI) values were 87.56% and 94.30%, respec-
as Sofosbuvir and Rilpivirine (Martin et al., 2002; Ramiz tively. These results were comparable to the positive con-
et al., 2011), antidiabetic such as Minoxidil (Abdel-Aziz trol, AZD9291, which had a TGI of 98.49 %, and they
et al., 2011; Hese et al., 2017), anticonvulsant properties showed that the drug had similar anticancer efficacy to
such as Thiopental and Phenobarbital (Alam et al., 2010; AZD9291. A1 compound also demonstrated significant
Sirakanyan et al., 2016), antioxidant properties (Bano pharmacokinetic properties with an AUC of 129.74 h ng/
et al., 2012; Kotaiah et al., 2012), and anticancer proper- ml, a half-life of 1.12 h, and bioavailability of more than
ties, such as Nilotinib (Abbas et al., 2021; Abdellatif & 70% with increased residence duration. Moreover, in sil-
Bakr, 2021; Ayati et al., 2021; Dongre et al., 2014). This ico modeling studies revealed U-shaped design of com-
review discusses the potential of pyrimidine derivatives pound A1 improved binding to the EGFR binding region
such as amino-linked and fused pyrimidine ring struc- of ATP due to the interaction sulfoxide group and the co-
tures in the development of EGFR tyrosine kinase inhib- valent nature of acrylamide moieties (An et al., 2019).
itors and their potential inhibition in non-small-cell lung Zhang et al. representing the cardiac toxicity of AZD9291
cancer (NSCLC). synthesized two groups of analogs based on AZD9291 in-
teractions with mutant EGFRL858R/T790M improving the
binding and selectivity were developed, where 2-amino
2 | A M I N O -P Y R IM IDIN E pyrimidine analogs showed better activity allowing for
DE RI VAT I V E S further ring expansion to reduce the cardio-toxic effects,
which resulted in compound A2 (Figure 5). Compound
2.1 | Amino-pyrimidine derivatives A2 was found to be less cardiotoxic than AZD9291 be-
cause it has lower binding affinities to the hERG ion chan-
An et al. were inspired by the pharmacological activity of nel. A2 exhibited in vitro inhibition based on enzymatic
sulfoxide, which led to the synthesis of a novel group of assay of EGFRT790M/L858R with an IC50 = 2.6 nM and
AZD9291 derivatives by incorporating sulfoxide substitu- NSCLC H1975 cell line with IC50 = 21.6 nM (Table 2).
tion at the C-4 position allowing the reduction of side ef- From metabolic stability studies in human and rat hepato-
fects of the AZD9291 compound. Out of 10 analogs cytes, A2 showed moderate microsomes stability and
synthesized, chiral compound A1 (Figure 5) exhibited pharmacokinetic properties with a bioavailability of more
F I G U R E 3 Structural overview of
pharmacophoric features of erlotinib
|
than 52.4% were reported. Furthermore, human NSCLC
Benzo pyrimidine, Amino pyrimidine


H1975 cell injected in vivo xenograft mouse model dem-
T A B L E 1 Overview of different stages of NSCLC and the use of different pyrimidine derivatives in application of these TKIS (DrugBank, 2022; National Cancer Institute, PDQ Adult
onstrated that A2 decreased tumor growth with a TGI of
96.3% at a dose of 20 mg/kg/day (Zhang et al., 2017).Gao
Pyrimidine derivatives
et al. referred to the metabolic pathways of osimertinib,
providing insights into the process taking place during the
Benzo pyrimidine
drug metabolized to form two key major metabolites,
which were taken into account to design and synthesis po-
tent compounds that avoid the N-methylation reaction in
N,N,N-trimethylethylenediamine and N-methylindole
substitution groups of osimertinib. Out of five compounds
synthesized, antiproliferative and kinase inhibition from
in vitro studies using compound A3 (Figure 5) exhibited
Erlotinib, Gefitinib, osimertinib, dacomitinib
Afatinib, dacomitinib osimertinib. olmutinib
the inhibitory potential of IC50 = 6.4 nM in double-mutant

Erlotinib, Gefitinib Afatinib, dacomitinib
EGFRL858R/T790M with moderate selectivity compared with

wild-type EGFR of IC50 = 318 nM (Table 2). In vivo experi-
ments using compound A3 in the NCI-H1975 cell injected
xenografts mice model showed a significant reduction in
tumor volume compared with osimertinib at a dose of
5 mg/kg/day. Docking studies of A3 revealed similar inter-
Erlotinib, Gefitinib
EGFR TKI used
action as of osimertinib with the addition of salt bridge

with mutant EGFR accounting for the stronger binding
Osimertinib
and better in vivo antitumor action (Gao et al., 2017). Zhao

et al. based on previous work based on binding mode anal-
ysis and docking studies of structures reported compounds
referring toward AZD9291 (Cross et al., 2014; Finlay
Combination of first and second generation of EGFR
Combination of first-, second-, and third-generation
of EGFR TKI along with chemotherapy or other
et al., 2014; Flanagan et al., 2014) allowing the synthesis of

TKI along with chemotherapy or other targeted
about three groups of pyrimidine compounds by structure-

based drug design approach on AZD9291 structure and
Second- and third-generation EGFR TKIs
evaluated using kinase and cellular assay in HepG2, A549,

and H1975 cell lines. The final compounds incorporated
various substituents groups at C-5 and C-6 regions of the
pyrimidine structure and modified the acrylamide side
First-generation EGFR TKIs
chain, where potent compound A4 showed antiprolifera-

tive action in H1975 cells at the G2/M phase and stimula-
targeted therapies
tion of apoptosis at a concentration of 0.25 μM and great

kinase inhibitory activity of EGFRL858R/T790M double mu-
Therapy used
therapies
tants with IC50 value of 8 nM (Table 2) and selectivity pro-

file of 200 folds compared with EGFRWT. The docking
studies demonstrated that compound A4 (Figure 5)
showed three hydrogen-bonded interactions among
Met793 and Cys797 of EGFR protein with the nitrogen
Del 19, L858R (Stage I-III)
EGFR positive NSCLC
atom of the pyrimidine ring, the hydrogen atom of the

Other point mutation
T790M (Stage I-III)
imine, and the oxygen atoms in the acrylamide side chains

C797S (Stage I-IV)
Treatment Editorial Board, 2002)
(Stage III-IV)
(Zhao et al., 2019). Singh et al. based on data obtained

from ligand-based pharmacophore models reported al-
lowed screening of an in-house database of 200 com-
pounds led by molecular dynamics identified indole
pyrimidines as a major scaffold, which allowed for further
substitution of aryl compounds. In vitro kinase inhibition
assay conducted with EGFRT790M revealed compounds A5
Sl. No
and A6 (Figure 5) were most potent compounds exhibit-

ing IC50 = 0.097 μM and IC50 = 0.094 μM (Table 2).
1
2
3
4
|
F I G U R E 4 Pyrimidine-ring-based
EGFR TK kinase inhibitors
Docking studies were done using Glide XP were com- synthesis of 5-(methylthio)pyrimidines analogs. The in-
pound A5 and A6 displayed higher binding affinity with troduction of methylthio substitution allowed effective
both hydrogen and hydrophobic interaction in the amino binding through hydrophobic interaction with the amino
group and indole moiety with EGFRT790M (Singh & acid of Met790 in mutant EGFRL858R/T790M accounting for
Silakari, 2018). Stolpovskaya et al. looked into amino py- hydrophobic, bulky attributes and special electrical inter-
rimidine fragment in EGFR TK inhibitors, thereby syn- action. All the synthesized derivatives exhibited less IC50,
thesizing a group of thiourea and thiazole-based amino and more selectivity compared to the reference, WZ4002
pyrimidine derivatives. In vitro data obtained identified and CO1686 in the enzymatic and cellular assay, out of
compounds, A7 and A8 (Figure 5) have inhibition rates of which fluorinated derivatives A15 and A16 (Figure 5) dis-
85–89% in EGFRL858R and 62%–76% in EGFRL858R/T790M in played potent inhibition in cell line H1975 with IC50 = 20
kinase assay conducted (Table 2; Stolpovskaya et al., 2019). and 88 nM (Table 2). On the other hand, compounds A17
Romu et al. utilizing WZ4002 structure allowed the design and A18 (Figure 5) exhibited potent inhibition at IC50 = 0.4
and synthesis of 32 derivatives of amino pyrimidine moi- and 0.7 nM in kinase assay (EGFRL858R/T790M) respectively
ety by incorporating electrophilic and non-electrophilic (Table 2; Xiao et al., 2016). Basu et al. designed and syn-
moieties with varied hydrophilic and lipophilic properties thesized covalent-based reversible inhibitors based on the
to expand the SAR of WZ4002. Biological evaluation by in structure of WZ4002. Out of the compounds synthesized,
vitro studies against a panel of six kinases EGFRWT, the most potent inhibition and selectivity were displayed
EGFRdelE746-A750, EGFRT790M, EGFRT790M/L858R, EGFRC797S, by cyano acrylamide groups, in which compound A19
and EGFRT790M/L858R/C797S and three cell lines PC9, (Figure 5) was having an IC50 of 37 nM (EGFRL858R/T790M;
PC9-GR, H460, wherein compound A9 (Figure 5) dis- Table 2; Basu et al., 2015). Zhou et al. aim to inhibit meta-
played potent action with inhibition at IC50 = 10 μM in all bolic reactions and N-demethylation, 18 novel osimertinib
six-kinase assay, while compounds A10, A11, A12, A13 analogs were created. The design strategy was adopted by
(Figure 5) showed triple mutant inhibition of changing the indole substituent (substituting it with other
EGFRL858R/T790M/C797S at IC50 = 10 μM with almost full in- heterocycles compounds), alkoxy group (substituting it
hibition rates at IC50 = 1 μM. Furthermore, the cellular with difluoromethoxy and methoxy), and ring closure of
assay displayed compounds A10, A11, A12, A13 and A14 the of N,N,N-trimethylethylenediamine side chains.
(Figure 5) with IC50 < 4.5 μM in all the cell lines (Table 2; Osimertinib's N-dimethyl metabolites were produced and
Romu et al., 2017). Xiao et al. utilizing a structure-based tested for biological activity. In both enzymatic and cellu-
design approach using WZ4002 allowed the design and lar studies, A20 (Figure 5) and its primary metabolites
|
F I G U R E 5 Structural representation
of 2-amino-pyrimidine derivatives
indicated over 30-fold selectivity with IC50 = 2.1 μM IC50 = 0.20, 0.015, and 0.14 μM in the PC-9, HCC827 and
(against mutant EGFRL858R/T790M over EGFR WT; Table 2). NCI-H1975 indicating a promising candidate for clinical
Also A20 demonstrated in vitro antitumor activity with testing (Table 2; Zhou, Chen, et al., 2018).
|
T A B L E 2 Biological activity of 2-amino-pyrimidine derivatives (An et al., 2019; Basu et al., 2015; Cross et al., 2014; Finlay et al., 2014;
Flanagan et al., 2014; Gao et al., 2017; Romu et al., 2017; Singh & Silakari, 2018; Stolpovskaya et al., 2019; Xiao et al., 2016; Zhang et
al., 2017; Zhao et al., 2019; Zhou, Chen, et al., 2018)
Compound EGFR type IC50/% inhibition Cell line IC50 inhibition

L858R/T790M
A1 EGFR 10 nM H1975 4.10 nM
A2 EGFRL858R/T790M 2.6 nM H1975 21.6 nM
L858R/T790M
A3 EGFR 6.4 nM H1975 17.5 nM
L858R/T790M
A4 EGFR 8 nM H1975 0.25 μM
A5 EGFRT790M 0.097 μM a a
A6 EGFRT790M 0.094 μM a a
L858R a a
A7 EGFR 89%
EGFRL858R/T790M 62%
L858R a a
A8 EGFR 86%
L858R/T790M
EGFR 76%
delE746-A750
A9 EGFR 100% at 10 μM PC9 <4.5 μM
A10 EGFRT790M PC9-GR, H460
Ba/F3-WT
A11 EGFRT790M L858R
Ba/F3-T3151
A12 EGFRC797S
A13 EGFRT790M/C797S/L858R
A14
A15 EGFRT790M/L858R 2.8 nM H1975 20 nM
A16 EGFRT790M/L858R 3.8 nM H1975 88 nM
T790M/L858R
A17 EGFR 0.4 nM H1975 0.167 μM
A18 EGFRT790M/L858R 0.7 nM H1975 0.194 μM
T790M/L858R a a
A19 EGFR 37 nM
L858R
A20 EGFR 5.5 μM H1975 0.14 μM
EGFRT790M/L858R 2.1 μM PC-9 0.20 μM
HCC827 0.015 μM
a
Study was not conducted/study conducted on nonspecific cell lines.
2.2 | 4-Amino-pyrimidine derivatives compounds involving diamino pyrimidine with the addi-
tion of modified aryl groups were filtered by drug-likeness
Novel azole diphenyl pyrimidine derivatives were synthe- and ADMET properties and assessment of cardiotoxicity.
sized based on the lead rociletinib by Song et al. Docking This resulted in the synthesis of 12 novel molecules and
data showed hydrogen bond formation with azole deriva- evaluation by in vitro cellular and enzymatic assays in
tives improving the binding affinity toward EGFRT790M. H1975and A549 cell lines where two compounds B2 and
Out of the eight analogs, B1 (Figure 6) was the most B3 (Figure 6) demonstrate IC50 of 0.56 and 0.62 and 0.88
potent inhibitor of dual mutant EGFRT790M/L858R pro- and 0.91 μM in dual mutant EGFRT790M/L858R (Table 3).
viding IC50 of 3.3 nM and reducing the multiplication Additional data of docking showed reversible binding
of H1975 of EGFRT790M at 0.118 μM (Table 3). B1 also with met793 indicating potency on EGFR inhibition (Patel
showed minimized T790M-induced drug resistance in et al., 2018). A series of 24 derivatives were synthesized
cell lines (A431WT, H1975L858R/T790M, A549k-ras muta- from preliminary docking data of irreversible EGFRT790M
tion) and increased selectivity about 300-fold toward inhibitors and IGF1R inhibitors with a good selectivity
mutant EGFRT790M compared with EGFR wild type al- profile to develop a dual inhibitor of EGFRT790M/IGF1R
lowing reduced the side effects (Song et al., 2016). Patel with 2,4-diarylamino-pyrimidines core. Compound B4
et al. accounting for the cardiotoxic effect observed dur- (Figure 6) showed exhibited great inhibitory action in ki-
ing increased dose of third-generation EGFR tyrosine nases assay with an IC50 value of 0.038 μM, along with sig-
kinase inhibitors allowed for structure-based virtual nificant anti-tumor effects toward H1975-IGF1R cell lines
screening based on the lead structure of osimertinib of IC50 = 0.013 mM with moderate selectivity index based
and literature survey were done with a dataset of 108 on a group of 468 kinases (Table 3). Based on structural
|
of 2,4-amino-pyrimidine derivatives
analysis, it was confirmed that the lipophilic substitution of NSCLC showing about 60% selectivity over wild-type
of a chlorine atom at the C-5 position of the pyrimidine EGFR (Table 3). Both B5 and B6 compounds displayed
ring and the NH substituent present at the C-4 position marked TGI in a dose-dependent manner in H1975 xeno-
was beneficial for the inhibition of the compound mak- graft mouse model, in vivo. In addition, B5 and B6 did not
ing it valuable as a new lead compound dual IGF1R induce mortality, significant weight loss, or any toxicity
and EGFRL858R/T790M inhibitors (Chan et al., 2015). A ra- and thus, these two compounds may be potential drug can-
tionalized study based on the application of three-step didates for EGFRT790M mutant NSCLC (Chen et al., 2017).
structure-based design molecules was done from precur- A group of morphine-substituted pyrimidine derivatives
sory structure to obtain more than 27 molecules were syn- was developed referencing rociletinib using flexible link-
thesized and structurally analyzed from which B5 and B6 ers and addition of morpholine ring in place of piperazine
(Figure 6) were found to have potential activity with IC50 ring, within the twelve structure synthesized compounds
of 4.1 and 3.2 nM with EGFRL858R/T790M mutant cell line B7 (Figure 6) exhibited potent inhibition and selectivity
|
toward double-mutant EGFRL858R/T790M with IC50 of in cellular assay respectively (Table 3; Ai et al., 2020).
0.71 nM compared with wild-type EGFR IC50 = 448.7 nM Zhou et al. optimized and synthesized diamino pyrimi-
(Table 3), thereby reducing the side effects. Moreover, dine derivatives, of the compounds synthesized it was
producing good inhibitory action of EGFRT790M muta- B10 (Figure 6) that displayed IC50 of 4 nM with 22 times
tion IC50 = 0.037 mM in H1975 cells (Table 3). Structural preference over EGFRWT (Table 3). Furthermore, a cellu-
studies revealed the presence of morpholine-substituted lar assay revealed compound B10 inhibits phosphoryla-
aniline at C-2 position was the reason for the distinct tion at IC50 of 41 nM and antiproliferative action at IC50
selectivity of compound B7. In vivo data of B7 showed of 37 nM against the H1975 cell line (Table 3). Docking
similar TGI value of 64.6% as that of rociletinib (70.15%) data showed interaction by forming covalent linkages
in H1975 (EGFR T790M) xenograft mice model without with Cys797 and three hydrogen bonds with Met 793
any impact on body weight, mortality and well tolerated and Gln791 by anilinopyrimidine core structure (Zhou,
(Song et al., 2017). Utilizing a fragment-based drug design Zhang, et al., 2018). Shao et al. based continual strategy
approach Ai et al. developed and synthesized a group of of chemical modulation designed and synthesized a group
diphenylpyrimidine derivatives, the biological evalua- of diaryl amino-pyrimidines with halogens, aliphatic and
tion revealed compounds B8 and B9 (Figure 6) having phenyl substitution at acrylamide to reduce off-target
IC50 = 3.89 and 7.13 nM EGFRT790M in kinase assay and binding and toxicity. In vitro data revealed that compound
H1975 cell line IC50 = 0.333 and 0.478 μM H1975 cell lines B11 (Figure 6) has IC50 of 3.9 nM in EGFRL858R/T790M and
IC50 of 0.75 nM NCIH1975 cell lines with cell cycle inhibi-
T A B L E 3 Biological evaluation of 2,4-amino-pyrimidine tion at phase G0/G1 (Table 3). Docking results showed the
derivatives (Ai et al., 2020; Chan et al., 2015; Chen et al., 2017; Patel interaction of 2 hydrogen bonds by aminopyrimidine core
et al., 2018; Shao et al., 2020; Song et al., 2016, 2017; Zhou, Zhang, and formation of covalent bonds with C797 with chloro-
et al., 2018) acrylamide linkage (Shao et al., 2020).
IC50 IC50
Compound EGFR type inhibition inhibitiona
B1 EGFRL858R/T790M 3.3 nM 0.118 μM
2.3 | 2, 6-Amino-pyrimidine derivatives
B2 EGFRL858R/T790M 0.56 μM 0.88 μM Four derivatives were synthesized based on substitu-
L858R/T790M
B3 EGFR 0.62 μM 0.91 μM tion on the core structure of quinazoline with 4,6 di-
B4 EGFRL858R/T790M 0.038 μM 0.13 mM aminopyrimidine of lead AZD3759 compound utilizing
B5 EGFR L858R/T790M
4.1 nM 0.184 μM scaffold hopping technique. After preparation of N4,
B6 EGFR L858R/T790M
3.2 nM 0.276 μM N6-disubstituted pyrimidines were screened for phar-
B7 EGFRL858R/T790M 0.71 nM 0.0037 μM
macological action. Compound C1 (Figure 7) showed
T790M the most potent activity in cell and enzyme assay show-
B8 EGFR 3.89 nM 0.333 μM
ing IC50 of below 1.5 nM in H3255, A431, HCC827, PC9,
B9 EGFRT790M 7.13 nM 0.478 μM
L858R/T790M
H1975 cell lines, and IC50 of 7.7 and 18 nM with mutants
B10 EGFR 4 nM 37 nM EGFRdelE746-A750 and EGFRL858R. Furthermore, com-
L858R/T790M
B11 EGFR 3.9 nM 0.75 nM pound C1 displayed prevention of EGFR-downstream
a
H1975 cell lines. communication through inhibition of phosphorylation
of 2, 6-amino-pyrimidine derivatives
|
in the xenograft mouse model. Binding interaction was showed IC50 of 2.11 and 0.93 μM in H226 and HCC827G
verified by molecular docking studies demonstrating cell lines of NSCLC. Molecular docking data revealed hy-
the hydrophobic interaction amino group at the C-6 po- drogen bonding interaction among NH of 4-phenylamine
sition (Zhang, Lv, Luo, et al., 2018). Another research and the neighboring hydrophobic pockets interaction
conducted synthesized 33 new derivatives of 4,6 diami- with 2, 6-dichlorophenyl moiety of the annulated pyrimi-
nopyrimidine compound based on structural evaluation dine rings (Xie et al., 2020).
of EGFR and FGFR inhibitors. Series of compounds were
developed having 4-urea aniline and six anilines accom-
panied with methoxy, alkyl, and halogen substituents, 3 | QUINAZOLINE DERIVATI V E S
in which compound C2 (Figure 7) has 2,5-dimethoxy
substituents on 6-aniline and 2,6-dichlorophenyl substi- A group of 2 aryls 4 amino-substituted quinazoline-based
tution on 4-urea aniline has been selected as influential molecules was synthesized from afatinib to counteract
molecule exhibiting dual FGFR and EGFR inhibitor ac- triple mutant drug resistance in NSCLC. Out of 31 com-
tion as shown by the kinase and western blot analysis re- pounds synthesized. Molecules D1, D2 and D3 (Figure 8)
ports. Compound C2 produced above 90% inhibition at exhibited IC50 in nanomolar concentration with excel-
10 μM accounting for both wild-type and mutated EGFR lent selectivity. Docking analysis gave information about
of quinazoline derivatives
|
the interactions of quinazoline and diazole substituents showed IC50 = 1.94 μM in an H1975 cell line (Table 4).
with various amino acids. In vitro evaluation showed SAR of compounds synthesized denoted the importance
that molecule D3 had an IC50 of 3.3 and 1.2 μM in dual of trifluoromethyl group substitution and docking stud-
mutant (L858R/T790M) and triple mutant (L858R/ ies revealed additional hydrogen bond interaction in
T790/C797S) cell lines (Table 4). Microsomal stability mutant EGFR due to sulfonamide linkage leading to
studies in liver microsomes of various species such as better binding action (Zhang et al., 2021). Song et al.
humans, rats and mice, revealed that compound D3 ex- to improve the selectivity of EGFR mutations synthe-
hibits good metabolic stability with a half-life of more sized a few triazole-linked quinazoline derivatives from
than 30 min. During in vivo pharmacokinetic studies quinazoline-based kinase inhibitors by click chemistry.
using male Sprague-Dawley rats established the phar- The compound synthesized was evaluated for kinase in-
macokinetic properties (half-life: 0.9 h, systemic clear- hibition assay showed that compound D7 (Figure 8) with
ance: 14,700 ml/min/kg, AUC of 353 h.ng/ml) with poor IC50 of 4 nM (EGFRL858R/T790M), anti-proliferative activity
bioavailability of 18.6% (Zhang et al., 2020). Parawa et al. with IC50 of 505 nM in H1975 cell line and 0.9 nM in PC9
to overcome the limited selectivity of second-generation cell lines respectively (Table 4; Song et al., 2019). Wang
EGFR-TKIs toward EGFR mutant and wild-type syn- et al. design and synthesis of Quinazoline Derivatives
thesized group of acrylamides substituted quinazolines with 4-Aniline linkage based on SAR of Gefitinib. Out of
using scaffold hopping approach, out of compounds syn- the which synthesized D8 compound (Figure 8) showed
thesized D4 and D5 (Figure 8) were showing promising an IC50 of 0.07 and 0.02 μM in cellular antiproliferative
results with in vitro studies with IC50 = 0.171 μM and IC50 assay A431 and HCC827cell lines respectively (Table 4;
0.159 μM in NCI-H1975 (EGFR L858R/T790M) cell lines Wang et al., 2016). For improving the EGFRT790M in-
and kinase inhibition with IC50 = 0.0062 and 0.0057 μM hibitory action, Lui et al. designed and synthesized a
in EGFR (L858R/T790M; Table 4). Furthermore, com- group of quinazoline derivatives referencing gefitinib
pound D5 stability was tested by MD studies indicating and erlotinib, in which biological evaluation identi-
100 ms and covalent linking of thiol substituent in the fied compound D9 (Figure 8) having IC50 = 4.3 nM in
C797 region (Pawara et al., 2021). Zhang et al. utiliz- EGFRL858R/T790M kinase assay and cellular assay with
ing the hybridization method synthesized three sets of IC50 values of 8.70, 13.45, 0.65, and 32.42 μM in H1975,
benzene-sulfonamide moiety-linked quinazoline deriva- A431, HCC827, and A549 cell lines (Table 4). Docking
tives as dual EGFR/CIAX inhibitors. In vitro data dis- analysis observed the binding interaction by the forma-
played that compound D6 (Figure 8) showed prominent tion of covalent and hydrogen bonds acrylamide group
action against EGFRT790M mutant IC50 value of 9.2 nM and quinazoline core moieties (Liu et al., 2018). Qin et al.
in kinase inhibition study which is 41 folds greater synthesized a group of fused quinazoline analogs and as-
than gefitinib and like osimertinib, while cellular assay sessed them for kinase inhibition activity. Compounds
T A B L E 4 Biological evaluation of
Compound EGFR type IC50 inhibition Cell line IC50 inhibition
quinazoline derivatives (Liu et al., 2018;
L858R/T790M/C797S
Pawara et al., 2021; Qin et al., 2016; Song D1 EGFR 0.44 μM H1975 20.3 μM
et al., 2019; Wang et al., 2016; Zhang et H1975(CTL) 12.6 μM
al., 2020, 2021) D2 EGFRL858R/T790M/C797S 0.69 μM H1975 20 μM
H1975(CTL) 10.1 μM
D3 EGFRL858R/T790M/C797S 0.63 μM H1975 3.3 μM
H1975(CTL) 1.2 μM
D4 EGFRL858R/T790M 57 nM H1975 0.171 μM
L858R/T790M
D5 EGFR 62 nM H1975 0.159 μM
D6 EGFRT790M 9.2 nM H1975 1.94 μM
L858R/T790M
D7 EGFR 4 nM H1975 505 nM
PC-9 0.9 nM
a a
D8 HCC827 0.02 μM
L858R/T790M
D9 EGFR 4.3 nM H1975 8.70 μM
HCC827 0.65 μM
D10 EGFRL858R/T790M 0.880 μM a a
L858R/T790M a a
D11 EGFR 0.336 μM
a
Study was not conducted/study conducted on nonspecific cell lines.
|
D10 AND D11 (Figure 8) had an IC50 value of 0.880 and binding site of mutant EGFRC797S (Lu et al., 2018). Hu
0.336 μM (Table 4). Docking data revealed good binding et al. investigated the structural aspects of a group of
interaction by compound D11 but not as effective as ge- 2-oxo-3, 4-dihydropyrimido [4, 5-d] pyrimidines de-
fitinib (Qin et al., 2016). rived from JND3229 (L1). Out of the compounds syn-
thesized, compound L2 (Figure 9) exhibited potently
inhibited EGFRL858R/T790M/C797S kinase bearing IC50 of
4 | P Y RI M IDO -P Y R IM IDIN E 3.1 nmol/L and anti-proliferation of Ba/F3 cells having
DE R I VAT I V E S EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S mutants
with IC50 values of 290 and 316 nmol/L. Furthermore,
Lu et al. outlining the resistance by C797S mutation in L2 inhibited the phosphorylation step in both
EGFR protein underwent virtual screening of an in- EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S in BaF3
house database holding 3000 compounds from which cells (Hu et al., 2020). Hao et al. created a group of py-
compound L1 was identified as a pyrimidopyrimidi- rimido [4,5-d] pyrimidine-2,4 (1H, 3H)-diones that were
none derivative. Compound L1 (Figure 9) subdued the developed with hydrophobic substituents at the N-6
propagation in EGFRL858R/T790M/C797S at IC50 at 5.8 nM, position based on the scaffold hopping strategy. In the
Ba/F3 (EGFRL858R/T790M/C797S) at IC50 at 0.31 μM, Ba/ compound L3 (Figure 9), potent inhibition action with
F3 EGFR19D/T790M/C797S mutations at IC50 at 0.51 μM, a selective profile (263-fold) was reported in biological
and H1975 (EGFRL858R/T790M) at IC50 at 0.32 μM being evaluation studies, reporting a significant IC50 of 0.3 nM
more effective than osimertinib and brigatinib refer- and an IC50 of 44 nM in H1975 cells demonstrated ex-
ences. Animal studies using a xenograft mouse model ceptional antiproliferative effect in the H1975 xenograft
of BaF3 cells showed the efficacy of L1 as a mono- mouse model, with TGI = 73% and p .001. However,
drug antitumor activity. The docking studies displayed there was less antitumor effectiveness (TGI = 37% and
that compound L1 possesses both hydrogen bonding p .05) in the A431 xenograft mouse model over 2 weeks
and as well as hydrophobic interactions with the ATP (Hao et al., 2018).
of pyrimido-pyrimidine derivatives and
their IC50 assay values
|
5 | F URO - P Y R IM IDIN E N,N-dimethyl amino group showed potent inhibition with

DE R I VAT I V E S EGFRL858R/T790M IC50 = 48 nM, HCC827 CC50 = 25 nM,
H1975 CC50 = 620 nM (Table 5). The compound F3 also
Lin et al. investigated the development of an in-house displayed an improved pharmacokinetic profile, giving
furanopyrimidine database, in which the identification a fourfold increase (AUC = 2978 ng/ml*h) than afatinib
of hit compound F1 with the (S)-2-phenylglycinol func- reference (AUC = 676 ng/ml*h) in oral AUC and oral
tional group is responsible for EGFR inhibition activity. bioavailability of 41.5%. Moreover, compound F3 showed
Compound F1 (Figure 10) undergone optimization by in- remarkable anticancer efficacy at doses of 20 and 50 mg/
corporation of acrylamide as substituent group at phenyl kg with slight toxicity in both HCC827 and H1975 xeno-
ring attached towards C-5 position of furanopyrimidine graft nude mice models. As of now, compound F3 is in
structure giving the lead compound F2 having good inhi- clinical trials (Lin et al., 2019). Han et al. designed and
bition shown by in vitro assays but showed poor in terms synthesized several 6-aryl-furo [2,3-d] pyrimidine-4-
of pharmacokinetic studies, allowing modification of lead amines, Significant inhibition of EGFR was shown by
compound F2 to improve the ADME properties by using compounds F4 and F5 (Figure 10) having stereocenters
scaffold hopping approach and structure-based drug de- at the 4-benzylamino region with IC50 = 0.4 and 0.6 nM
sign approach led to synthesizes a group of fused pyrimi- in the kinase assay (Table 5). Molecular dynamics simu-
dine synthesized, in which compound F3 (Figure 10) with lation displayed that π interactions were responsible for
F I G U R E 1 0 Structural
representation of furo-pyrimidine
derivatives
|
T A B L E 5 Biological evaluation
Compound EGFR type IC50/Ki Cell line IC50/CC50
of furo-pyrimidine derivatives (Han
F1 EGFRL858R/T790M >10,000 nM HCC827 518 nM et al., 2016; Hanan et al., 2016; Lin et
L858R/T790M al., 2019)
F2 EGFR 2 nM HCC827 H1975 24 nM
1258 nM
F3 EGFRL858R/T790M 48 nM HCC827 H1975 25 nM
620 nM
F4 EGFRL858R/T790M 0.4 nM Ba/F3 216
L858R/T790M
F5 EGFR 0.6 nM Ba/F3 197
F6 EGFRL858R/T790M 2 nM H1975 0.6 μM
L858R/T790M
F7 EGFR 9 nM H1975 0.37 μM
the inhibition activity. The following compounds F4 and of less than 1000 nM (Table 6). This was further proved
F5 (Figure 10) also exhibited marked activity in the Ba/ by docking analysis, which displayed that compounds
F3 cell line with EGFRL858R mutation with IC50 at 217 and E3 and E6 produced more polar hydrophobic binding
196 nM respectively (Han et al., 2016). Hanan et al. discov- compared to olmutinib. Furthermore, compound E6
ered 4-aminoindazolyl-dihydrofuro[3,4-d] pyrimidine de- allowed inhibition of cluster growth, lesion recovery,
rivatives via an internal database-based virtual screening, and the upregulation of p-EGFR and its downstream
with compound F6 (Figure 10) demonstrating Ki of 2 nM signaling in H1975 cell lines with the EGFRL858R/T790M
and IC50 of 0.60 M in the H1975 cellular assay but poor mutation (Chen et al., 2020). Xiao et al. designed and
pharmacokinetic properties were observed through in vivo synthesized five groups of novel thiophene-pyrimidine
studies (Table 5). To improve the pharmacokinetic profile molecules and evaluated them by in vitro assays in
of lead compound F6, a structure-based design approach various cell lines. Out of 30 molecules synthesized com-
was used, as well as metabolite studies. This leads to the pound E7 (Figure 11) displayed the most potent activ-
addition of various heterocyclic rings at the C-2 and C-4 ity in A549 and A431 cell lines at an IC50 value of 4.34
locations of the pyrimidine compound. In vitro analysis al- and 3.79 μM (Table 6). Compound E7 also resembled
lowed the identification of three compounds as having po- olmutinib, demonstrating high activity and selectivity
tent inhibitory action with an IC50 of below 9 nM whereas profile towards EGFRT790M and EGFRT790M/L858R muta-
compound F7 (Figure 10) displayed an IC50 of 0.37 nM in tion in EGFR. Furthermore, studies revealed that E7
H1975 in a cellular assay (Table 5; Hanan et al., 2016). caused dose-dependent late apoptosis in A431 cancer
cells (Xiao, Zhou, et al., 2020). Wu et al. discovered hit
compound E8 (Figure 11) from high throughput screen-
6 | T H I E N O -P Y R IM IDIN E ing and optimized it to get a series of analogs with incor-
DE RI VAT I V E S poration of chiral side chain of phenylaminoethanol and
hybridization strategy with a compound obtained from
Milik et al. referencing the drug lapatinib (dual EGFR/ counter screening approach. SAR study of compounds
HER2 inhibitor) synthesized a group of 6-phenylthieno in this group of compounds displayed the involvement
[2, 3-d] pyrimidine, out of the compounds synthe- of side-chain groups such as phenyl, hydroxyl, and stere-
sized compound E1 (Figure 11) obtained a significant ocenters phenylaminoethanol allowed for the increased
IC50 with 91.7 and 1.2 nM in EGFR and HER2 as- potency leading to compound E9 (Figure 11) with IC 50
says (Table 6). Moreover, reports showed good anti- of 0.007, 0.305, 0.002 μM in EGFRwt, EGFRL858R/T790M,
proliferative action in NCI-H1975 cell lines having and HCCC827 (EGFRdelE746-A750) cell lines respectively
lapatinib resistance and T790M mutation (IC50 = 4.2 μM; (Table 6; Leu et al., 2020).
Table 6), allowing deactivation of EGFR phosphoryla-
tion and downstream signaling with a linear increase in
dose (Milik et al., 2018). Using a conformational con- 7 | PYRROLO - P YRIMIDINE
strained method, Chin et al. designed and synthesized DERIVATIVES
a novel thieno [3,2-d] pyrimidines based on olmutinib,
a third-generation EGFR inhibitor. A total of 18 com- Based on an earlier design study, Ann Christin et al.
pounds were synthesized, of which compounds E2, E3, added novel groups of 5-Aryl-7H-pyrrolopyrimidin-4-a
E4, E5, and E6 (Figure 11) showed a potent inhibition mines followed by synthesis. Docking data showed com-
rate toward mutant EGFRL858R/T790M with an IC50 of pounds having a strong binding with two main binding
less than 250 nM and significant selectivity at an IC50 modes obtained by changing the position of 4-amino
|
representation of thieno-pyrimidine
derivatives
T A B L E 6 Biological evaluation of
Compound EGFR type IC50 Cell line IC50
thieno-pyrimidine derivatives (Chen
et al., 2020; Leu et al., 2020; Milik et E1 EGFR 91.7 nM A439 1.45 μM
al., 2018; Xiao, Zhou, et al., 2020) H1975 4.2 μM
E2 EGFRL858R/T790M 0.25 μM H1975 4.15 μM
L858R/T790M
E3 EGFR 0.11 μM H1975 10.89 μM
E4 EGFRL858R/T790M 0.20 μM H1975 10.76 μM
L858R/T790M
E5 EGFR 0.24 μM H1975 10.05 μM
E6 EGFRL858R/T790M 0.23 μM H1975 10.78 μM
L858R
E7 EGFR 65 nM A431 3.79 μM
EGFRL858R/T790M 13.6 nM A549 4.39 μM
E8 EGFRL858R >10 μM HCCC827 >10 μM
EGFRL858R/T790M
E9 EGFRL858R/T790M 0.305 μM HCCC827 0.002 μM
and 6-aryl groups. A propagation study using NSCLC than erlotinib by H1 and H2 (Figure 12) compounds
cells Ba/F3-EGFRL858R, revealed similar action to that of (Reiersølmoen et al., 2019). Cheng et al. described the
Erlotinib by 3-hydroxy substituted derivative H1 inhibit- improvement of pyrrolo-pyrimidine EGFR TK inhibitors
ing with an IC50 of 0.9 nM. In vitro analysis indicated that with the H3 compound. In silico docking, data revealed
3-hydroxy and 4-methoxy derivatives, H1 had an IC50 the hydrophobic interactions between Met790's side chain
of 112 nM and H2 had an IC50 of 104 nM in Ba/F3 cells and the pyrrolo-pyrimidine moiety, which allowed for el-
with mutant EGFRL858R. Furthermore, a screening assay evated levels of T790M inhibitory potential as well as the
with over 50 kinases, revealed a greater selectivity profile selectivity profile. Moreover, additional hydrogen bond
|
representation of pyrrole-pyrimidine
derivatives and their IC50 assay values
representation of thiopyrano-pyrimidine
derivatives and their IC50 assay values
interactions were displayed by Gln791 amino acid at the a dual active screening, compound I1 (Figure 13) showed
ATP binding pocket of the mutant EGFRT790M. Cellular inhibition with an IC50 of 4.22 μM and an IC50 of 2.19 μM
assays conducted showed potency against NSCLC cell in cellular assays of A549 and H1975, respectively, and a
lines H1975 (L858R/T790M) with IC50 of 13 nM, PC9- potent inhibitory effect of more than 90% in conjunction
DRH (Del/T790M) with IC50 of 7 nM, H3255 (L858R) with with an IC50 of 1 nM against mutant EGFRL858R/T790M. I1
IC50 of 21 nM, PC9 (Del) with IC50 of 140 nM, HCC827 demonstrated the anti-proliferative activity of the H1975
(Del) with IC50 of 90 nM also revealed poor selectivity pro- cell line in the G2/M phase and dose-dependent induction
file in wild-type EGFR cells A549 (EGFRWT) with IC50 of of apoptosis. Docking results found that I1 bound more
5100 nM respectively. Compound H3 (Figure 12) has been closely and firmly with hydrogen bond interactions with
shown to have antiproliferative properties comparable to Met-793 and Arg-841 in EGFRT790M and resembled the in-
the standard drugs rociletinib, osimertinib, and erlotinib teraction of olmutinib (Xiao, Chu, et al., 2020). Bingbing
(Cheng et al., 2016). et al. using structure-based drug design on lead molecules
AZD9291 and BMC-20142422-7e, designed and synthe-
sized four groups of thiopyrano-pyrimidines together
8 | T H I O P YR AN O -P Y R IM IDINE with various substituted acrylamide moieties. Docking
D E R I VAT I V E S studies revealed an H-bond contact with the Met793
amino acid of the EGFRT790M. These modifications were
Zhen et al. worked on the synthesis of a group of thiapyran- made by adding aliphatic heterocycles into the pyrimidine
pyrimidine derivatives, which was designed based on the ring of AZD9291 and side-chain substituents to increase
docking evaluation of 3rd generation EGFR TK inhibitors the size of the pyrimidine ring to fully occupy the protein
with special emphasis on the olmutinib structure, allowing binding site and reduce toxicity and off-targeting of com-
for the incorporation of the thiopyran-pyrimidine moiety pounds while producing a potent compound. In vitro data
in place of thiophene-pyrimidine and side-chain modifi- provided by selected compound I2 (Figure 13) displayed
cation at the C-2 position. From the in vitro data based on showed potent kinase inhibition and selectivity profile
|
for EGFRL858R/T790M double mutations with an IC50 of EGFR tyrosine kinase inhibitors in the newly devel-
16 nM, with a selectivity of more than 125-fold. Moreover, oped C797S mutant resistance in EGFR protein using
compound I2 displayed anti-proliferative activity at IC50 a structure-based design approach. The basic structure
values of 0.057 and 0.916 μM in inhibited A549 cells and was represented as 4-Aminopyrazolo-pyrimidine sub-
H1975 cells (Zhao et al., 2020). stituted with N-acrylamide-Piperidine, considering the
binding interaction of the ATP binding region of EGFR
followed by the incorporation of lipophilic substitu-
9 | P Y RA ZO LO -P Y R IM IDIN E tion at the C-3 side. The in vitro assay found J4, J5, and
D E R I VAT I V E S J6 (Figure 14) to have beneficial inhibitory effects on
H1975 cells with the EGFRL858R/T790M mutation, hav-
Gaber et al. developed three groups of pyrazolo [3,4-d] ing GI50 values of 0.21, 0.49, and 0.14 μM and J6 showed
pyrimidine derivatives whose structures were modified IC50 of 88nM in EGFRL858R/T790M/C797S. Docking data dis-
at C-2 and C-4 positions by the attachment of different played a covalent bond with Cys797 towards the front
substituent groups. The majority of molecules synthe- side of the hinge region of the binding site. According
sized inhibit EGFRWT mostly, with sub-micromolar IC50 to studies, these three compounds had profound effects
values equivalent to erlotinib, although only J1, J2, and in inhibiting phosphorylation and downstream commu-
J3 (Figure 14) displayed compounds inhibited mutant nication pathways related to EGFR in H1975 cells while
EGFRT790M in a manner comparable to osimertinib with having a low selective action against the A431 cell line
IC50 values of 3.2, 2.72, 3.9 nM. Moreover, a prolifera- (EGFRWT; Engel et al., 2016).
tion inhibition study in three cancer cell lines (HepG2,
MCF7, and A549 having EGFRWT) and two NSCLC
cell lines (HCC827 and H1975 with EGFRT790M) was 10 | PYRIDO - P YRIMIDINE
conducted. Five compounds showed the highest anti- DERIVATIVES
cancer potential against the EGFRWT cells, while com-
pounds J1, J2, and J3 showed antiproliferative potential Zhang et al. designed and synthesized a novel pyrido
against mutant EGFRT790M containing cells (H1975 [3,4-d] pyrimidine core structure as irreversible EGFR-
and HCC827) with an IC50 range of 0.02–0.09 μM. TKIs incorporating acrylamide substitution to account
Docking data showed favorable binding scores vary be- for EGFRT790M resistance. Out of the compounds syn-
tween −19.27 and −27.46 kcal/mol (Gaber et al., 2018). thesized, the K1 (Figure 15) compound showed potent
Engel et al. designed and synthesized three pyrazolo- IC50 = 0.025 μM in HCC827 and IC50 = 0.49 μM in H1975
pyrimidine molecules to produce covalently bonded cell lines. The compound also inhibited EGFRL858R with
representation pyrazolo-pyrimidine and
|
representation of pyrido-pyrimidine and
an IC50 of 1.7 nM and EGFRL858R/T790M with an IC50 of A431 (EGFRWT) IC50 of 1200 nM (100 times selectiv-
23.3 nM. In vivo studies show compound K1 at a dose of ity). Activity study towards a panel of kinases showed
50 mg/kg exhibits potent tumor shrinkage (TGI of 60.6% KD of 220 and 0.96 nM in EGFRWT and EGFRT790M.
and 86.5% at doses of 10 and 50 mg/kg respectively) in the Pharmacokinetic profile demonstrated good oral bioa-
HCC827 xenograft mouse model. Furthermore, in vivo vailability and 90% suppression of tumor on the admin-
studies declares that compound K1 did not cause any istration of 30 mg/kg daily in H1975 xenograft model
mortality and no significant body weight loss indicating (Wurz et al., 2015).
that K1 was well tolerated with low toxicity at all doses.
Docking studies revealed hydrogen (Met793), hydropho-
bic, and Van der Waals(Phe856& Asp855) interactions 11 | MISCELLANEOUS
as responsible for the strong inhibition induced (Zhang, DERIVATIVES
Wang, Zhao, et al., 2018). Zhang et al. have synthesized a
group of pyrido [3, 4-d] pyrimidine derivatives, in which Apart from the above-discussed pyrimidine derivatives
compound K2 (Figure 15) demonstrated an inhibition which have potential EFGR tyrosine kinase inhibition
rate at an IC50 of 0.004 μM in HCC827 (EGFRdelE746-A750) activity in mutant strains, they were other pyrimidine-
and 0.40 μM in H1975 (EGFRL858R/T790M) cell lines. K2 linked compounds reported in research studies that
also showed inhibitory activity against EGFRL858R at an were investigated for advancement in the development
IC50 value of 1.1 nM and EGFRL858R/T790M/C797S with an of newer pyrimidine-based EGFR tyrosine kinase inhibi-
IC50 value of 7.2 nM. In silico studies revealed that R2's tors. Pyrimidine-2-one group-based groups were synthesis
hydroxyl group allows for H-bond along mutant Ser797 and evaluated, in which two compounds had comparable
in the EGFRL858R/T790M/C797S protein. Furthermore, cel- inhibition action of standard drugs erlotinib and osimer-
lular assay in HCC82 showed dose-related interference tinib in kinase assay (IC50 = 0.110 & 0.058 μM EGFRWT,
in phosphorylation and incite apoptosis (Zhang, Wang, IC50 = 0.038 & 0.087 μM EGFRL858R, and IC50 = 0.044 &
Shen, et al., 2018). Wurz et al. designed and synthe- 0.026 μM EGFRT790M; Othman et al., 2021). Fused qui-
sized oxopyridopyrimidine series of compounds. where nolones with pyrimidine moiety were identified as the
compound K3 (Figure 15) was exhibiting potent IC50S best compound exhibiting great potency in kinase and
of 4 and 28 nM in H1975(EGFRL858R/T790M) and HCC827 cellular assays IC50 of 0.053 μM EGFRL858R and IC50 of
(EGFRdelE746-A750) cell lines in anti-proliferation assay 0.026 μM EGFRT790M and IC50 of 4.96 μM in H1975 cell
with a good preference towards mutant strain than lines (Shaheen et al., 2020). Nasser et al. worked on the
|
design and synthesis of pyrimidine-5-carbonitrile based CONFLICT OF INTEREST

compounds, in which one compound showed marked in- The authors declare that they have no known competing
hibition action with IC50 2.4 μM in the A549 cell line and financial interests or personal relationships that could
screened for kinase activity with IC50 of 0.09 and 4.03 μM have appeared to influence the work reported in this
against EGFRWT and EGFRT790M (Nasser et al., 2020). fur- paper.
thermore, indole and imidazole fused pyrimidine rings
have shown promising inhibition in EGFRWT cell lines DATA AVAILABILITY STATEMENT
I nanomolar scale values with can consider in optimiz- Data sharing is not applicable to this article as no new data
ing for mutant EGFR protein (Ahmed et al., 2021; Kalra were created or analyzed in this study. The article is a re-
et al., 2020). view on the research works related to pyrimidine deriva-
tives in this area (non small cell lung cancer).
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EJMECH.2017.04.036

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Received: 23 March 2022

| Revised: 11 July 2022

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors

Anandu Kizhakkedath Ratheesh | Ajay Pottankottu Jayan |

Amrita School of Pharmacy, Amrita

1 | I N T RO DU CT ION after moderate progression of cancer. Imaging and tissue

than 52.4% were reported. Furthermore, human NSCLC

Benzo pyrimidine, Amino pyrimidine

Benzo pyrimidine, Amino pyrimidine

the inhibitory potential of IC50 = 6.4 nM in double-­mutant

EGFRL858R/T790M with moderate selectivity compared with

action as of osimertinib with the addition of salt bridge

and better in vivo antitumor action (Gao et al., 2017). Zhao

et al., 2014; Flanagan et al., 2014) allowing the synthesis of

about three groups of pyrimidine compounds by structure-­

evaluated using kinase and cellular assay in HepG2, A549,

chain, where potent compound A4 showed antiprolifera-

tion of apoptosis at a concentration of 0.25 μM and great

tants with IC50 value of 8 nM (Table 2) and selectivity pro-

atom of the pyrimidine ring, the hydrogen atom of the

imine, and the oxygen atoms in the acrylamide side chains

(Zhao et al., 2019). Singh et al. based on data obtained

and A6 (Figure 5) were most potent compounds exhibit-

Compound EGFR type IC50/% inhibition Cell line IC50 inhibition

5 | F URO - P ­ Y R IM IDIN E N,N-­dimethyl amino group showed potent inhibition with

design and synthesis of pyrimidine-­5-­carbonitrile based CONFLICT OF INTEREST

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the inhibitory potential of IC50 = 6.4 nM in double-mutant

about three groups of pyrimidine compounds by structure-

5 | F URO - P Y R IM IDIN E N,N-dimethyl amino group showed potent inhibition with

design and synthesis of pyrimidine-5-carbonitrile based CONFLICT OF INTEREST