Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader
Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of <b>ZLC491</b> as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. The compound effectively degraded CDK12 and CDK13 with DC<sub>50</sub> values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that <b>ZLC491</b> selectively induced CDK12/13 degradation in a cereblon- and proteasome-dependent manner. Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, <b>ZLC491</b> achieved an oral bioavailability of 46.8% in rats and demonstrated potent <i>in vivo</i> degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.
Authors
- Ke Ding (ORCID: https://orcid.org/0000-0001-9016-812X)
- Licheng Zhou (ORCID: https://orcid.org/0000-0002-8145-5124)
- Arul M. Chinnaiyan (ORCID: https://orcid.org/0000-0001-9282-3415)
- Jianzhang Yang
- Somnath Mahapatra (ORCID: https://orcid.org/0000-0001-9490-6353)
- Ming Ding (ORCID: https://orcid.org/0000-0002-9135-9275)
- Yu‐Sun Chang (ORCID: https://orcid.org/0000-0002-6457-3890)
- Zilu Li
- Fengtao Zhou (ORCID: https://orcid.org/0000-0003-2518-7855)
- Rahul Mannan (ORCID: https://orcid.org/0000-0002-6642-0468)
- George Xiaoju Wang
- Jian Xu (ORCID: https://orcid.org/0000-0003-1816-4129)
- Xiaomei Ren (ORCID: https://orcid.org/0000-0002-0963-4144)
- Kaijie Zhou
- Zhen Wang (ORCID: https://orcid.org/0000-0001-8762-6089)
- Yuhan Su (ORCID: https://orcid.org/0000-0003-1866-4748)
- Bohai Fan
- Weixue Huang (ORCID: https://orcid.org/0000-0003-4884-6585)
- Jinwei Zhang (ORCID: https://orcid.org/0009-0005-1520-2881)
Institutions
- Howard Hughes Medical Institute (US)
- Jinan University (CN)
- China Pharmaceutical University (CN)
- Chinese Academy of Sciences (CN)
- University of Michigan (US)
- Shanghai Institute of Organic Chemistry (CN)
- Michigan Center for Translational Pathology (US)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01596
- Citations
- 15
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 3.51
Funders
- Howard Hughes Medical Institute
- American Cancer Society
- Prostate Cancer Foundation
- A. Alfred Taubman Medical Research Institute
- National Natural Science Foundation of China
- Shenzhen Bay Laboratory
- National Key Research and Development Program of China
- National Cancer Institute