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