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Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader
Licheng Zhou1,2, Kaijie Zhou2,3, Yu Chang4,5
1International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, China.
Abstract:
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 ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. The compound effectively degraded CDK12 and CDK13 with DC50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that ZLC491 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, ZLC491 achieved an oral bioavailability of 46.8% in rats and demonstrated potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.
Insights
Researchers developed ZLC491, a novel orally available PROTAC degrader targeting CDK12/13. This compound shows promise for treating triple-negative breast cancer by selectively degrading key proteins and inhibiting cancer cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) is a promising therapeutic strategy for triple-negative breast cancer (TNBC).
- Existing proteolysis-targeting chimera (PROTAC) degraders for CDK12/13 lack oral bioavailability.
Purpose of the Study:
- To discover and characterize a novel, orally bioavailable PROTAC degrader targeting CDK12/13.
- To evaluate the efficacy of the novel degrader in preclinical models of TNBC.
Main Methods:
- Synthesis and characterization of ZLC491, a PROTAC degrader.
- In vitro degradation assays in TNBC cells (MDA-MB-231) to determine DC50 values.
- Global proteomic analysis and mechanistic studies.
- Cell proliferation assays.
- Pharmacokinetic studies in rats and in vivo efficacy studies in a mouse xenograft model.
Main Results:
- ZLC491 potently and selectively degraded CDK12/13 in TNBC cells (DC50 values of 32 and 28 nM).
- Degradation was cereblon- and proteasome-dependent.
- ZLC491 suppressed transcription of long genes, particularly those involved in DNA damage response, and inhibited TNBC cell proliferation.
- The compound exhibited 46.8% oral bioavailability in rats and demonstrated in vivo target engagement in a xenograft model.
Conclusions:
- ZLC491 is a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader.
- ZLC491 demonstrates significant anti-cancer activity in preclinical TNBC models.
- This discovery offers a potential new therapeutic avenue for TNBC and other cancers.
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