Design, Synthesis, In Vitro, and In Silico Studies of New <i>N</i>⁵-Substituted-pyrazolo[3,4-<i>d</i>]pyrimidinone Derivatives as Anticancer CDK2 Inhibitors

• Main Authors: Waheed A. Zaki (Author), Selwan M. El-Sayed (Author), Mohamed Alswah (Author), Ahmed El-Morsy (Author), Ashraf H. Bayoumi (Author), Abrahman S. Mayhoub (Author), Walaa H. Moustafa (Author), Aeshah A. Awaji (Author), Eun Joo Roh (Author), Ahmed H.E. Hassan (Author), Kazem Mahmoud (Author)
• Format: Book
• Published: MDPI AG, 2023-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph16111593; 1424-8247
• Keywords: anticancer agents; liver cancer; colorectal cancer; CDK2; pyrazolo[3,4-<i>d</i>]pyrimidine analogs; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 16, Iss 11, p 1593 (2023)

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-<i>d</i>]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-<i>d</i>]pyrimidinone derivatives bearing <i>N</i>⁵-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds <b>4a</b> and <b>4b</b> confirmed their CDK2 inhibitory activity. Compound <b>4a</b> 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 <b>4a</b> and <b>4b</b> with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds <b>4a</b> and <b>4b</b> 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.