Page 111 - Pharma News Letter - Vol2 Issue 1

Research Publications

Design, Synthesis, In Vitro, And In Silico Studies Of New N5-
Substituted-Pyrazolo[3,4-D]Pyrimidinone Derivatives As
Anticancer Cdk2 Inhibitors

Pharmaceuticals. 2023; 16(11): 1593.
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Waheed A. Zaki, Selwan M El-Sayed, Mohamed Alswah, Ahmed El-Morsy, Ashraf H.
Bayoumi, Abrahman S. Mayhoub, Walaa H. Moustafa, Aeshah A. Awaji, Eun Joo Roh,

Ahmed H.e. Hassan, Kazem Mahmoud

Abstract

CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various
cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers
that affect humans worldwide. The available therapeutic options suffer from many drawbacks
including high toxicity and decreased specificity. Therefore, there is a need for more effective
and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed,
synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and
HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N5-2-(4-halophenyl)
acetamide substituents were identified as the most potent amongst evaluated compounds. Further
evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed
their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine
regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In
silico molecular docking provided insights into the molecular interactions of compounds 4a
and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and
Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting
antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for
future further investigations and development.

Reference:

https://doi.org/10.3390/ph16111593

Vol. 2 - Issue 1 111