CYCLIN-

DEPENDENT KINASE 2

07/11/2024 1
Introduction
Cyclin-dependent kinase (CDK) is a serine/threonine protein kinase family with a total of 20
members, including CDK1-CDK20. CDK family cooperates with cyclin and plays an
important role in the regulation of cell cycle. CDKs and cyclins are usually overexpressed in
cancer cells. Therefore, CDKs’ inhibitors have been considered as promising candidate
drugs for cancer treatment.

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Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 (CDK2) is an important member of the CDK family.

CDK2 is a core cell cycle regulator in dividing cells, which is highly active from the late G1
phase to the entire S phase and counteracts cell cycle exit induced by DNA damage.

It also has roles in inactivating phosphorylation of the RB1 (pRb) tumour suppressor family.

Moreover, there is a lot of evidence that the activity of CDK2 also affects cell differentiation
and adaptive immune responses.

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Acting on CDK2
Clinical studies have found that overexpression of CDK2 can lead to tumors.

Most CDK2 inhibitor candidates target the ATP binding site and can be divided into two
main subclasses: type I and type II.

CDK2 is shown in blue, with the Asp-Phe-Gly (DFG) motif in green. Red color
0 7 /11 /2 0 2 4 denotes the aspartate amino acid residue of the DFG motif. Sample Footer Text 4
Acting on CDK2
Type I inhibitors competitively target the ATP binding site in its active state. In this state,
the DFG sequence fits snugly into a hydrophobic back pocket adjacent to the ATP binding
site.

Type II inhibitors target CDK2 in its unbound (inactive) state, where DFG motif swings
outwards by partially blocking both the ATP and substrate binding pockets either
occupying the ATP binding site or hydrophobic pocket within the kinase.
Type II inhibitors are believed to be more selective.

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Acting on CDK2
Recently, the availability of new CDK crystal structures led to the identification of a
potential allosteric binding site near ATP binding site. Inhibitors of this allosteric site are
classified as type III inhibitors.

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Approved drugs
Flavopiridol is a semisynthetic flavonoid structurally related
to a naturally occurring alkaloid isolated from a plant (Dysoxylum
binectariferum) indigenous to India.

The binding of the drug at the active site of CDK2 for response. The
chlorine atom of flavopiridol favourably interacts with the active site
of CDK2, which may be one of the reasons for the increased kinase
inhibition by flavopiridol

The chiral hydroxyl moiety on the ring has been found to be

essential for the anti CDK activity of flavopiridol.
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Roscovitine [seliciclib]
It is abroad-range purine inhibitor, roscovitine is widely
used as a biological tool in cell cycle, cancer, apoptosis
Buried surface of CDK2 and the inhibitor shows a very
close fit on the area around the benzyl ring suggesting that
the ring is a moiety which increases the specificity for
CDK2.
Isopropyl appears to be the most active substituent.

Structure/activity studies confirm that n7 of the purine ring

must remain free of substitution.

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Milciclib is an orally bioavailable inhibitor of cyclin-
dependent kinase 2 (CDK2). It is a potential candidate for
HCC which exhibits inhibitory activity against CDK2.

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 3D IMAGE SHOWING
INTERACTION
BETWEEN COMPOUND
8
AND CDK2
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3D IMAGE SHOWING
INTERACTION
BETWEEN
COMPOUND 8A AND
CDK2
INTERACTIONS
1-TWO HYDROGEN BOND INTERACTIONS THE 2-AMINOTHIAZOL MOIETY INTERACTS WITH THE KEY AMINO ACID
LEU83 BACKBONE.{ IC50 = 0.93 ΜM}

2-FORM A WATER-MEDIATED HYDROGEN BOND WITH THE KEY AMINO ACID ASP145
BACKBONE NH USING THEIR CARBONYL GROUP IN POSITION 5 OF THE THIAZOLE
RING.

3-INTERACT WITH THEIR COUMARIN RING THROUGH HYDROGEN

BONDING WITH LYS89 NH3+ AND THROUGH HYDROPHOBIC INTERACTION WITH
THE HYDROPHOBIC SIDE CHAINS OF ILE10, VAL18, AND GLN85 WHAT
RATIONALIZES THAT THE BROMO SUBSTITUTION AT THE COUMARIN NUCLEUS GIVES
THE HIGHEST CYTOTOXIC

4-THE METHYL GROUP ON POSITION 4 OF THE THIAZOLE RING IS FITTED IN THE

VICINITY OF THE HYDROPHOBIC SIDE CHAINS OF THE AMINO ACIDS ALA31, VAL64
AND PHE80 ACHIEVING A HYDROPHOBIC INTERACTION WITH THESE SIDE CHAINS.

5-THAT THE ACTIVITY DECREASES WITH THE DECREASE IN

THE HYDROPHOBICITY OF THE SUBSTITUENT ON THE COUMARIN RING.
• Code 2A4L

• Classification: TRANSFERASE

• Organism(s): Homo sapiens

• Method: X-RAY DIFFRACTION

• Resolution: 2.40 Å

• R-Value Free: 0.270

• R-Value Work: 0.173

• R-Value Observed: 0.173

• Ligand:RRC

• Human cyclin-dependent kinase 2 in complex

with roscovitine
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Code 1DM2
Classification: CELL CYCLE
Organism(s): Homo sapiens
Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.267
R-Value Work: 0.192
R-Value Observed: 0.192 Ligand:
HMD
Human cyclin-dependent kinase 2
complexed with the inhibitor
Hymenialdisine
Code 1CKP
Classification:
HORMONE/GROWTH FACTOR
Organism(s): Homo sapiens
Method: X-RAY DIFFRACTION
Resolution: 2.05 Å
R-Value Free: 0.260
R-Value Work: 0.192 R-
Value Observed: 0.192
HUMAN CYCLIN DEPENDENT
KINASE 2 COMPLEXED WITH
THE INHIBITOR PURVALANOL B
Code 1aq1
Classification: Protein kinase
Organism(s): Homo sapiens
Method: X-ray diffraction
Resolution: 2.00 Å
R-Value Free: 0.260
R-Value Work: 0.220
Ligand STU
Human cyclin dependent kinase 2
complexed with the inhibitor
Staurosporine

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Code 1OIQ
Classification: KINASE
Organism(s): Homo sapiens
Method: X-RAY DIFFRACTION
Resolution: 2.31 Å
R-Value Free: 0.271
R-Value Work: 0.227
R-Value Observed: 0.229
Ligand : HDU
Imidazopyridines: a potent and selective class of
Cyclin-dependent Kinase inhibitors identified
through Structure-based hybridisation
Code 1E1X
Classification: PROTEIN KINASE
Organism(s): Homo sapiens
Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free: 0.281
R-Value Work: 0.213
Ligand NW1
HUMAN CYCLIN DEPENDENT KINASE 2
COMPLEXED WITH THE INHIBITOR NU6027
Øconclusion
Ø According to the previous slides, it's obvious that Amino acid (Leu-83
and ) -that make hydrogen bond- is repeated in sex codes{2A4L-1DM2-
1CKP-1E1X-1OIQ-1AQ1}
Ø Amino acid {glu_81}-that make hydrogen bond- is repeated in three
codes (1DM2-1AQ1-1E1X)
Ø so if we need to design a drug, we should take it in consideration.
 THANK
YOU

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REFERENCES
 https://atm.amegroups.com/article/view/6314/html

 https://pubs.rsc.org/en/content/articlelanding/2018/nj/c8nj04306j

 https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01254

 https://www.researchgate.net/figure/A-B-Two-dimensional-2D-and-three-dimensional-3D-intera
ction-diagrams-of-docked_fig2_351201630