Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors

Bioorg Med Chem. 2024 Apr 3;104:117711. doi: 10.1016/j.bmc.2024.117711. Online ahead of print.ABSTRACTCyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.PMID:38583237 | DOI:10.1016/j.bmc.2024.117711
Source: Bioorganic and Medicinal Chemistry - Category: Chemistry Authors: Source Type: research