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

• Published in: Nature communications 2024-08, Vol.15 (1), p.6477-13, Article 6477
• Main Authors: Zhang, Zemin, Li, Yuanqing, Yang, Jie, Li, Jiacheng, Lin, Xiongqiang, Liu, Ting, Yang, Shiling, Lin, Jin, Xue, Shengyu, Yu, Jiamin, Tang, Cailing, Li, Ziteng, Liu, Liping, Ye, Zhengzheng, Deng, Yanan, Li, Zhihai, Chen, Kaixian, Ding, Hong, Luo, Cheng, Lin, Hua
• Format: Article
• Language: English
• Subjects: 13/1; 631/92/2783; 631/92/612; 631/92/613; Adhesives; Cell Line, Tumor; Cell Proliferation; Cyclin-dependent kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - metabolism; Cyclins; Damage detection; Degradation; Deoxyribonucleic acid; DNA; DNA damage; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Drug development; Drug discovery; Glues; Humanities and Social Sciences; Humans; Kinases; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Protein Binding; Protein folding; Protein interaction; Proteins; Science; Science (multidisciplinary); Stabilization; Tumor cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50642-0

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. Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery. Here, the authors propose a dual-site approach for the design of clyclin K molecular glues, targeting the PPI region and its dynamic surroundings, and report a dual-site molecular glue for the cyclin-dependent kinase 12 - DNA damage-binding protein 1 complex, resulting in further cyclin K degradation.