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

  • J Med Chem. 2025 Jun 12;68(11):11586-11605. doi: 10.1021/acs.jmedchem.5c00472.
Jing Xu  1  2  3 ,  Ye Zhong  1 ,  Mengdi Qin  4 ,  Yufei Zhang  5 ,  Yinuo Ma  6 ,  Baichun Hu  1 ,  Qiang Fu  4 ,  Yili Sun  3  5  7 ,  Maosheng Cheng  1 ,  Yang Liu  1 ,  Jia Li  2  3  6  7
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 4. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 5. School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230011, China.
  • 6. Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250000, China.
  • 7. Stake Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 40392624 DOI: 10.1021/acs.jmedchem.5c00472
Abstract

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.

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