Discovery and Administration Optimization of Novel Selective CDK9 Inhibitor, 1-7a-B1, for Improved Pharmacokinetics and Antitumor Efficacy <i>In Vivo</i>
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 (IC<sub>50</sub> = 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 <i>in vivo</i>. 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.
Authors
- Qiang Fu (ORCID: https://orcid.org/0000-0003-4076-5609)
- Mengdi Qin
- Baichun Hu (ORCID: https://orcid.org/0000-0001-8959-6979)
- Ye Zhong (ORCID: https://orcid.org/0009-0006-7074-1922)
- Yili Sun (ORCID: https://orcid.org/0000-0002-0198-2734)
- Maosheng Cheng (ORCID: https://orcid.org/0000-0001-9073-4806)
- Yufei Zhang (ORCID: https://orcid.org/0000-0002-1163-1807)
- Yang Liu (ORCID: https://orcid.org/0000-0002-9284-1944)
- Jing Xu (ORCID: https://orcid.org/0000-0003-4907-8688)
- Jia Li (ORCID: https://orcid.org/0000-0002-2652-0034)
- Yifeng Ma (ORCID: https://orcid.org/0009-0009-6412-3943)
Institutions
- Shenyang Pharmaceutical University (CN)
- Academy of Medical Sciences (GB)
- Chinese Academy of Sciences (CN)
- Anhui University of Traditional Chinese Medicine (CN)
- Shanghai Institute of Materia Medica (CN)
- Advanced Research Institute (US)
- Shandong First Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00472
- Citations
- 1
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 1.52
Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Taishan Scholar Foundation of Shandong Province
- Key Technology Research and Development Program of Shandong