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Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13

Jianzhang Yang1, Yu Chang1,2, Jean Ching-Yi Tien2,3

  • 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, People's Republic of China.

Journal of Medicinal Chemistry
|August 8, 2022
PubMed

Insights

Researchers developed novel proteolysis-targeting chimeras (PROTACs) to selectively degrade cyclin-dependent kinases 12 and 13 (CDK12/13). The lead compound 7f shows potent degradation and anti-proliferation effects, offering a new therapeutic strategy for triple-negative breast cancer (TNBC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) is a promising therapeutic strategy for triple-negative breast cancer (TNBC).
  • A significant unmet need exists for dual CDK12/13 degraders in TNBC treatment.

Purpose of the Study:

  • To discover and characterize the first series of potent and selective dual CDK12/13 degraders using proteolysis-targeting chimera (PROTAC) technology.
  • To evaluate the efficacy of these degraders in TNBC cell lines.

Main Methods:

  • Design and synthesis of PROTACs targeting CDK12/13.
  • Assessment of compound potency and selectivity using biochemical assays and proteomic profiling in MDA-MB-231 cells.
  • Evaluation of *in vitro* anti-proliferative activity in multiple TNBC cell lines.

Main Results:

  • The optimal compound, 7f, demonstrated high potency in degrading CDK12 (DC50=2.2 nM) and CDK13 (DC50=2.1 nM).
  • Global proteomic profiling confirmed the target selectivity of compound 7f.
  • Compound 7f suppressed DNA damage response (DDR) gene expression and inhibited proliferation of TNBC cell lines (IC50=47 nM for MFM223), outperforming a similar inhibitor.

Conclusions:

  • The discovery of 7f represents the first series of potent and selective dual CDK12/13 degraders.
  • CDK12/13 degraders, exemplified by 7f, hold significant potential as a targeted therapy for triple-negative breast cancer.

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