In silico-driven identification of potent CDK9 inhibitors through bioisosteric replacement and multi-stage virtual screening.

ABSTRACT: Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase crucial for transcriptional elongation via phosphorylation of the C-terminal domain (CTD) of RNA polymerase II, thereby enabling productive mRNA synthesis. Given its pivotal role in gene expression, CDK9 represents a validated therapeutic target in cancer research. This study employed a sequential bioisosteric replacement strategy to identify novel CDK9 inhibitors. Initially, a library of 17,633 compounds was generated by replacing the core scaffold of 134 known inhibitors. Pharmacophore-based virtual screening reduced this set to 3,754 candidates, from which a highly predictive QSAR model identified compound 50224760_85 as the most promising lead. A second round of bioisosteric substitution yielded 66,966 novel structures, incr

SUBMITTER: Amorim J 

PROVIDER: S-EPMC12764791 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature