Discovery of a highly potent, selective, and stable d-amino acid-containing peptide inhibitor of CDK9/cyclin T1 interaction for the treatment of prostate cancer.

Cyclin-dependent kinase 9 (CDK9) plays a pivotal role in promoting oncogenic transcriptional pathways, significantly contributing to the development and progression of cancer. Given the unique biostability of d-amino acid, the development of d-amino acid-containing peptides (DAACPs) is a promising strategy for cancer treatment. Currently, no DAACPs inhibitor targeting CDK9-cyclin T1 have been reported. Here, we reported the identification of a novel, highly potent, selective and stable DAACPs inhibitor (peptide-5) targeting CDK9-cyclin T1 interaction. Peptide-5 showed nanomolar inhibitory effect against CDK9-cyclin T1 (IC = 4.16 ± 0.11 nM). Molecular dynamics (MD) simulation exhibited that peptide-5 stably bound to CDK9. Peptide-5 showed good inhibitory activity against multiple types of prostate cancer cells and demonstrated good biostability in mouse serum. Moreover, peptide-5 suppresses the tumor growth in DU145 cell-derived xenografts nude mice. These data suggest that peptide-5 is a potent antitumor candidate for further research.