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Cell Reports Medicine

Cell Reports Medicine

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

Published:15 October 2024 DOI: 10.1016/j.xcrm.2024.101752 PMID: 39353441
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

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.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
GSK2141795 1047634-65-0 C18H16Cl2F2N4O2 100 suppliers $28.00-$1950.00
GSK2141795 1047634-65-0 C18H16Cl2F2N4O2 100 suppliers $28.00-$1950.00
GSK2141795 1047634-65-0 C18H16Cl2F2N4O2 100 suppliers $28.00-$1950.00
GSK2141795 1047634-65-0 C18H16Cl2F2N4O2 100 suppliers $28.00-$1950.00
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