Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor

Eur J Med Chem. 2022 Jan 15;228:114012. doi: 10.1016/j.ejmech.2021.114012.

Tian Niu ¹, Kailin Li ¹, Li Jiang ¹, Zhesheng Zhou ¹, Ju Hong ¹, Xuankun Chen ¹, Xiaowu Dong ², Qiaojun He ³, Ji Cao ⁴, Bo Yang ⁵, Cheng-Liang Zhu ⁶

Affiliations

1 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
2 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
3 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Center for Drug Safety Evaluation and Research of ZJU, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China.
4 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China.
5 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
6 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Center for Drug Safety Evaluation and Research of ZJU, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China. Electronic address: [email protected].

PMID: 34864331 DOI: 10.1016/j.ejmech.2021.114012

Abstract

Cyclin-dependent kinase 12 (CDK12) plays a crucial role in DNA-damage response gene transcription and has recently been validated as a promising target in Cancer therapy. However, existing CDK12 inhibitors potently inhibit its closest isoform CDK13, which could cause potential toxicity. Therefore, the development of CDK12 inhibitors with isoform-selectivity against CDK13 continues to be a challenge. By taking advantage of the emerging PROteolysis-TArgeting Chimeras (PROTACs) approach, we have synthesized a potent PROTAC degrader PP-C8 based on the noncovalent dual inhibitors of CDK12/13 and demonstrated its specificity for CDK12 over CDK13. Notably, PP-C8 induces profound degradation of cyclin K simultaneously and downregulates the mRNA level of DNA-damage response genes. Global proteomics profiling revealed PP-C8 is highly selective toward CDK12-cyclin K complex. Importantly, PP-C8 demonstrates profound synergistic antiproliferative effects with PARP Inhibitor in triple-negative breast Cancer (TNBC). The potent and selective CDK12 PROTAC degrader developed in this study could potentially be used to treat CDK12-dependent cancers as combination therapy.

Keywords

CDK12; Cyclin K; PROTAC; Synthetic lethality; Triple-negative breast cancer.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-144691

PP-C8

99.99%, PROTAC CDK12-Cyclin K Degrader

PROTACs; CDK

Cancer

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