Identification of a Potent and Selective CDK9 Degrader as a Targeted Therapeutic Option for the Treatment of Small-Cell Lung Cancer
Small-cell lung cancer (SCLC) represents a significant public health challenge due to its increasing incidence and high mortality. Most SCLC patients are diagnosed at advanced stages, and there are limited effective targeted therapies available. In this study, a potent and selective CDK9 degrader, <b>C3</b>, was developed through PROTAC modification of the CDK9 inhibitor, AT-7519. <b>C3</b> effectively induced apoptosis in various SCLC cell lines at low nanomolar concentrations and demonstrated favorable <i>in vivo</i> tolerance and adequate oral bioavailability. Notably, PROTAC <b>C3</b> significantly reduced the proliferation of primary tumor samples from patients in mini-PDX models. Our findings indicate that the targeted degradation of CDK9 could become a viable strategy for treating SCLC, highlighting its potential therapeutic value. Additionally, this research offers a general structural optimization and evaluation strategy to improve the degradative selectivity, metabolic stability, and oral availability of PROTAC molecules.
Authors
- Yubo Wang (ORCID: https://orcid.org/0000-0002-0895-8745)
- Shuangwei Liu
- Kun Zhang (ORCID: https://orcid.org/0000-0003-2401-1858)
- Sheng Cao (ORCID: https://orcid.org/0000-0003-1047-5862)
- Guang Yang (ORCID: https://orcid.org/0000-0002-1773-9392)
- Ma Lan
- Shuxin Zhang (ORCID: https://orcid.org/0000-0003-4715-9070)
- Yan Zhang (ORCID: https://orcid.org/0000-0002-6535-7866)
- Mengmeng Wang (ORCID: https://orcid.org/0000-0002-3636-4370)
- Yinghui Yang (ORCID: https://orcid.org/0000-0002-9827-9980)
- Yue Jiao (ORCID: https://orcid.org/0009-0007-5902-6722)
- Jialu Li (ORCID: https://orcid.org/0000-0002-6411-6876)
- Mingming Wei
Institutions
- Nankai University (CN)
- State Key Laboratory of Chemical Engineering (CN)
- Zaozhuang University (CN)
- State Key Laboratory of Medicinal Chemical Biology
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01621
- Citations
- 7
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Science and Technology Foundation of Shenzhen City
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Ningbo Municipal Bureau of Science and Technology
- International Science and Technology Cooperation Programme