Discovery and Administration Optimization of Novel Selective CDK9 Inhibitor, 1‑7a-B1, for Improved Pharmacokinetics and Antitumor Efficacy In Vivo

Cyclin-dependent kinase 9 (CDK9) is a member of the transcriptional CDK subfamily. In this work, a de novo design strategy was used to obtain a series of novel CDK9 inhibitors. A novel selective CDK9 inhibitor named 1-7a-B1, which possesses significant CDK9 inhibitory activity (IC50 = 6.51 nM), was developed. Research on the mechanism revealed that 1-7a-B1 could induce apoptosis in the HCT116 cell line by inhibiting the phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related gene and protein expression, and these results were validated at the cellular and tumor tissue levels. Furthermore, a 1-7a-B1-based submicrometer emulsion system was successfully developed on the basis of its ADME properties for improved pharmacokinetics and antitumor efficacy in vivo. This study provides a solution for an oral administration strategy for molecules with strong first-pass elimination. Currently, this emulsion system is being researched further for CRC treatment.