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

• Published in: Cell reports. Medicine 2024-10, Vol.5 (10), p.101752, Article 101752
• Main Authors: Chang, Yu, Wang, Xiaoju, Yang, Jianzhang, Tien, Jean Ching-Yi, Mannan, Rahul, Cruz, Gabriel, Zhang, Yuping, Vo, Josh N., Magnuson, Brian, Mahapatra, Somnath, Cho, Hanbyul, Dhanasekaran, Saravana Mohan, Wang, Cynthia, Wang, Zhen, Zhou, Licheng, Zhou, Kaijie, Zhou, Yang, Zhang, Pujuan, Huang, Weixue, Xiao, Lanbo, Liu, Weihuang Raymond, Hamadeh, Rudana, Su, Fengyun, Wang, Rui, Miner, Stephanie J., Cao, Xuhong, Cheng, Yunhui, Mehra, Rohit, Ding, Ke, Chinnaiyan, Arul M.
• Format: Article
• Language: English
• Subjects: Administration, Oral; AKT; AKT inhibitors; Animals; Biological Availability; CDC2 Protein Kinase; CDK12; CDK13; 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; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; PROTAC; Proteolysis - drug effects; proteolysis targeting chimera; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Synthetic Lethal Mutations; synthetic lethality; Xenograft Model Antitumor Assays
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101752

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. [Display omitted] •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.