Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex

Zemin Zhang, Yuanqing Li, Jie Yang, Jiacheng Li, Xiongqiang Lin, Ting Liu, Shiling Yang, Jin Lin, Shengyu Xue, Jiamin Yu, Cailing Tang, Ziteng Li, Liping Liu, Zhengzheng Ye, Yanan Deng, Zhihai Li, Kaixian Chen, Hong Ding (), Cheng Luo () and Hua Lin ()
Additional contact information
Zemin Zhang: Fujian Medical University
Yuanqing Li: Nanjing University of Chinese Medicine
Jie Yang: Fujian Normal University
Jiacheng Li: Chinese Academy of Sciences
Xiongqiang Lin: Fujian Medical University
Ting Liu: Fujian Medical University
Shiling Yang: Fujian Normal University
Jin Lin: Fujian Medical University
Shengyu Xue: Nanjing University of Chinese Medicine
Jiamin Yu: Nanjing University of Chinese Medicine
Cailing Tang: Nanjing University of Chinese Medicine
Ziteng Li: Chinese Academy of Sciences
Liping Liu: Chinese Academy of Sciences
Zhengzheng Ye: University of Chinese Academy of Sciences
Yanan Deng: University of Chinese Academy of Sciences
Zhihai Li: University of Chinese Academy of Sciences
Kaixian Chen: Nanjing University of Chinese Medicine
Hong Ding: Chinese Academy of Sciences
Cheng Luo: Fujian Medical University
Hua Lin: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.

Date: 2024
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DOI: 10.1038/s41467-024-50642-0

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