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 M. Dhanasekaran, Cynthia Wang, Zhen Wang, Licheng Zhou, Kaijie Zhou, Yang Zhou, Pujuan Zhang, Weixue Huang, Lanbo Xiao, W Liu, Rudana Hamadeh, Fengyun Su, Rui Wang, Stephanie J. Miner, Xuhong Cao, Yunhui Cheng, Rohit Mehra, Ke Ding, Arul M. Chinnaiyan
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. • Development of an orally bioavailable CDK12/13 degrader (YJ1206) • YJ1206 exhibits minimal adverse effects in immune-competent mice • YJ1206 is efficacious in preclinical models of advanced prostate cancer • YJ1206 induces synthetic lethality in conjunction with AKT pathway inhibition Chang et al. develop YJ1206, an orally bioavailable degrader that exhibits high specificity in degrading CDK12/13 and demonstrates robust anti-tumor activity in vivo . The degradation of CDK12/13 leads to activation of the AKT pathway. YJ1206 in combination with AKT inhibitors achieves a striking synthetic lethal effect in prostate cancer models.