Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition

Yu Chang; Xiaoju Wang; Jianzhang Yang; Jean Ching-Yi Tien; Rahul Mannan; Gabriel Cruz; Yuping Zhang; Josh N Vo; Brian Magnuson; Somnath Mahapatra; Hanbyul Cho; Saravana Mohan Dhanasekaran; Cynthia Wang; Zhen Wang; Licheng Zhou; Kaijie Zhou; Yang Zhou; Pujuan Zhang; Weixue Huang; Lanbo Xiao; Weihuang Raymond Liu; Rudana Hamadeh; Fengyun Su; Rui Wang; Stephanie J Miner; Xuhong Cao; Yunhui Cheng; Rohit Mehra; Ke Ding; Arul M Chinnaiyan

doi:10.1016/j.xcrm.2024.101752

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition

Cell Rep Med. 2024 Oct 15;5(10):101752. doi: 10.1016/j.xcrm.2024.101752. Epub 2024 Sep 30.

Authors

Yu Chang¹, Xiaoju Wang², Jianzhang Yang³, Jean Ching-Yi Tien¹, Rahul Mannan¹, Gabriel Cruz¹, Yuping Zhang¹, Josh N Vo¹, Brian Magnuson¹, Somnath Mahapatra¹, Hanbyul Cho¹, Saravana Mohan Dhanasekaran², Cynthia Wang¹, Zhen Wang⁴, Licheng Zhou³, Kaijie Zhou⁴, Yang Zhou⁵, Pujuan Zhang⁴, Weixue Huang⁴, Lanbo Xiao¹, Weihuang Raymond Liu⁶, Rudana Hamadeh⁶, Fengyun Su¹, Rui Wang¹, Stephanie J Miner¹, Xuhong Cao⁷, Yunhui Cheng¹, Rohit Mehra⁸, Ke Ding⁹, Arul M Chinnaiyan¹⁰

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
² Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
³ State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China; School of Pharmaceutical Sciences, Jinan University, Guangzhou 511436, People's Republic of China.
⁴ State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China.
⁵ School of Pharmaceutical Sciences, Jinan University, Guangzhou 511436, People's Republic of China.
⁶ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA.
⁹ State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China. Electronic address: [email protected].
¹⁰ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].

Abstract

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells. CDK12/13 degradation rapidly triggers gene-length-dependent transcriptional elongation defects, leading to DNA damage and cell-cycle arrest. In vivo, YJ9069 significantly suppresses prostate tumor growth. Modifications of YJ9069 yielded an orally bioavailable CDK12/13 degrader, YJ1206, which exhibits comparable efficacy with significantly less toxicity. To identify pathways synthetically lethal upon CDK12/13 degradation, phosphorylation pathway arrays were performed using cell lines treated with YJ1206. Interestingly, degradation or genetic knockdown of CDK12/13 led to activation of the AKT pathway. Targeting CDK12/13 for degradation, in conjunction with inhibiting the AKT pathway, resulted in a synthetic lethal effect in preclinical prostate cancer models.

Keywords: AKT; AKT inhibitors; CDK12; CDK13; PROTAC; prostate cancer; proteolysis targeting chimera; synthetic lethality.

MeSH terms

Administration, Oral
Animals
Biological Availability
CDC2 Protein Kinase
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinases* / antagonists & inhibitors
Cyclin-Dependent Kinases* / metabolism
DNA Damage / drug effects
Humans
Male
Mice
Mice, Nude
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Proteolysis / drug effects
Proto-Oncogene Proteins c-akt* / genetics
Proto-Oncogene Proteins c-akt* / metabolism
Signal Transduction / drug effects
Synthetic Lethal Mutations*
Xenograft Model Antitumor Assays

Substances

Proto-Oncogene Proteins c-akt
CDK12 protein, human
Cyclin-Dependent Kinases
CDK13 protein, human
CDC2 Protein Kinase