Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex
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 ident...
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Published in | Nature communications Vol. 15; no. 1; pp. 6477 - 13 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.08.2024
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-024-50642-0 |