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

• DOI: 10.1016/j.xcrm.2024.101752
• Publication Date: 2024-09-30T14:42:08Z
• Authors: 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 Dh...; 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
• Keywords: Lethality; Synthetic Lethality

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