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

  • Cell Rep Med. 2024 Oct 15;5(10):101752. doi: 10.1016/j.xcrm.2024.101752.
Yu Chang  1 ,  Xiaoju Wang  2 ,  Jianzhang Yang  3 ,  Jean Ching-Yi Tien  1 ,  Rahul Mannan  1 ,  Gabriel Cruz  1 ,  Yuping Zhang  1 ,  Josh N Vo  1 ,  Brian Magnuson  1 ,  Somnath Mahapatra  1 ,  Hanbyul Cho  1 ,  Saravana Mohan Dhanasekaran  2 ,  Cynthia Wang  1 ,  Zhen Wang  4 ,  Licheng Zhou  3 ,  Kaijie Zhou  4 ,  Yang Zhou  5 ,  Pujuan Zhang  4 ,  Weixue Huang  4 ,  Lanbo Xiao  1 ,  Weihuang Raymond Liu  6 ,  Rudana Hamadeh  6 ,  Fengyun Su  1 ,  Rui Wang  1 ,  Stephanie J Miner  1 ,  Xuhong Cao  7 ,  Yunhui Cheng  1 ,  Rohit Mehra  8 ,  Ke Ding  9 ,  Arul M Chinnaiyan  10
Affiliations
  • 1. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China; School of Pharmaceutical Sciences, Jinan University, Guangzhou 511436, People's Republic of China.
  • 4. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China.
  • 5. School of Pharmaceutical Sciences, Jinan University, Guangzhou 511436, People's Republic of China.
  • 6. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 7. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 8. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China. Electronic address: [email protected].
  • 10. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
PMID: 39353441 DOI: 10.1016/j.xcrm.2024.101752
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.

Keywords
AKT; AKT inhibitors; CDK12; CDK13; PROTAC; prostate cancer; proteolysis targeting chimera; synthetic lethality.
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