Dual-targeting inhibitors: A new avenue in drug

therapy

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  Selective drugs against cancer cells should eradicate tumors
more specifically, reducing side effects in normal cells. However,
the inhibition of a single target often shows transient efficacy due
to the development of drug resistance.
 Targeting multiple signaling pathways, either with drug
combinations or through the design and development of a single
compound can be considered.

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J. Med. Chem. 2014, 57, 19, 7874–7887
 Drug combination therapy
 The approach in which two or more drugs are typically used in combination
 The combinational inhibition of two different pathways involved in disease progression often causes
synergistic or additive effects and can lower the potential for developing drug resistance.
Cons:
 Drugs might interfere with each other, thereby reducing efficacy
 Complicates dosing schedules and negatively impacts patient compliance;
 Acute and delayed toxicities may be higher in drug combinations, especially when combining drugs
are not selective
 Problems may also arise when two drugs are being developed by different pharma companies,
because regulatory and intellectual property issues may delay clinical trials of these investigational
drug combinations

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J. Med. Chem. 2014, 57, 19, 7874–7887
J. Med. Chem. 2022,
 Dual-target therapies
 Dual-target drugs are novel chemical entities that interact with two targets and feature better
therapeutic efficacy, lower dosages, and less tissue toxicity than single-target agents
 Selection strategy : bind with prespecified targets
 Based on the clinical data, phenotypic screening of drug combinations or in silico approaches.
 Rationale:

Show high efficacy and reduce the therapeutic doses and side effects compared to single-target
drug treatments.
To overcome incomplete efficacy
To overcome drug resistance frequently present with individual targeting agents
 Pros:

More predictable pharmacokinetic profile and safety profile compared to multiple molecules
administered in combination.
Cost-effective alternative to drug combinations
Probability of developing target-based resistance to multi-target drugs is statistically lower than
against single-target drugs
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J. Med. Chem. 2014, 57, 19, 7874–7887
J. Med. Chem. 2022,
 Multi-target therapy
 Polypharmacology
 Multi-target drugs, especially dual target inhibitors, have better dosage
flexibility, more predictable PK profiles, and lower adverse events while
ensuring therapeutic efficacy
 Commonly used strategies for developing multi-target inhibitors:
 High-throughput screening (HTS): Low efficiency
 Design of scaffold combinations: popular, two or more molecules are integrated into a
single molecule with multi-targeting properties
Integration methods: linked, fused, and merged types
 Maximum combination of pharmacophores is possible
 designing of more simplified compounds.

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J. Med. Chem. 2014, 57, 19, 7874–7887
J. Med. Chem. 2022,
 Peroxisome Proliferator Activated Receptors (PPAR)
 Nuclear hormone receptor with subtypes a, b and g
 PPAR a is involved in fatty acid beta-oxidation and is a major regulator of
energy homeostasis.
 PPAR b as target for controlling lipid, glucose and energy homeostasis
 PPAR g modulates lipid and carbohydrate metabolism and is molecular target
for thiazolidinedione (TZD) class of insulin sensitizing antihyperglycemic
agents
 Two pharmaceutically important PPAR g agonists, pioglitazone and
rosiglitazone, are blockbuster drugs

J. Med. Chem. 2005, 48, 3015-3025 6

Bioorganic & Medicinal Chemistry 15 (2007) 1547–1555
European Journal of Medicinal Chemistry 43 (2008) 2784-2791
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Epidermal Growth Factor Receptor (EGFR)
 EGFR also known as HER1 is a core member of the ErbB protein
kinase family that regulates multiple cellular behaviors, such as
cell growth, proliferation, and differentiation
 EGFR family members consist of a glycosylated extracellular
domain, a hydrophobic single-chain transmembrane region, and
an intracellular kinase domain.

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J. Med. Chem. 2022,
Dual EGFR/VEGFR-2 inhibitor

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 Zhang et al. added the diaryl-urea and glycine methyl ester part of
the VEGFR inhibitor pharmacophore into the kinase-selective
region at the 4-position of EGFR inhibitor vandetanib
 36 was obtained by introducing an alkaline solubilizing side chain
at position C-7 that extends to the solvent-accessible region to
increase the inhibitory activity against VEGFR-2.
 It possessed favorable inhibitory activity, with IC50 values of 1
and 79 nM against EGFR and VEGFR-2, respectively.
 In addition, the anti-proliferation activity against HT-29, MCF-7,
and H460 cell lines was 1.76, 7.28, and 26 μM, respectively
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 Histone Deacetylase (HDAC) inhibitors
 HDAC inhibitors have been developed, including Vorinostat,
Belinostat, Panabinostat, Valproic acid, etc

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Cancers 2021, 13, 634
 Vorinostat

pharmacophores from nitrogen mustard drugs to its

phenyl ring or cap group
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Cancers 2021, 13, 634
  Vorambucil showed slightly selective inhibitory activity against HDAC1 and
HDAC2 over HDAC6.
 It induced increased DNA damage compared to its parent compound
chlorambucil, and showed significantly enhanced anticancer potency in cell
growth inhibition assays.
 Vorambucil showed potent antiproliferative activity against HepG2, A549,
HCT116, and A375 cancer cells with IC50 values of 3.2-6.2 μM, and
displayed 5-18-fold enhanced antiproliferative activity compared to its parent
compound, chlorambucil.
 Also, vorambucil remarkably arrested the cell cycle and induced apoptosis of
A375 cells at the G2/M phase.

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Cancers 2021, 13, 634
Thank You!!

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 J. Med. Chem. 2005, 48, 3015-3025
 Bioorg. Med. Chem. 2007, 15, 1547–1555
 Eur. J. Med. Chem. 2008, 43, 2784-2791
 Bioorg. Med. Chem. Letts. , 2008, 18, 4959-4962
 Bioorg. Med. Chem. Letts., 2008, 18, 3192-3195
 Eur. J. Med. Chem., 2009, 44, 3488-3495
 Eur. J. Med. Chem., 2009, 44, 42-53
 Eur. J. Med. Chem. 2016, 108, 423-435
 J. Indian Chem. Soc., 2020, 97, 1191-1197

 J. Comput. Med. 2013, 2013

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 Smalley et al. designed and synthesized a series of class I-selective HDAC
degraders [284]. To this end, the class I-selective 2-aminoanilide CI-994 was
linked via alkyl linkers to either pomalidomide as a CRBN ligand or VH032 as
a Von Hippel-Lindau (VHL) E3 ligase ligand. The VH032-based PROTAC 4
(Figure 7), the most efficient degrader from this series, demonstrated at least
50% degradation of HDACs 1, 2 and 3 in HCT116 colon cancer cells at a
concentration of 1 µM. After a 48 h treatment, PROTAC 4 exhibited
comparable effects on HCT116 cell viability as its parent compound CI-994

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