Proteomics

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The CDK12-inhibitor CR8 mediates Cyclin K degradation through the CUL4-RBX1-DDB1 E3 ubiquitin ligase

ABSTRACT: Small molecules have been identified that induce protein-protein interactions between a substrate and a ubiquitin ligase, resulting in targeted protein degradation. Such molecular glue compounds, unlike traditional enzyme inhibitors, act sub-stoichiometrically to catalyse rapid depletion of previously inaccessible targets. Molecular glue degraders have the potential for clinical efficacy, but have thus far only been discovered serendipitously. Through correlations between compound cytotoxicity and E3 ligase expression levels, we found that CR8, a cyclin-dependent kinase (CDK) inhibitor, acts as a molecular glue degrader. A surface-exposed pyridyl moiety of CR8 is sufficient to induce complex formation between CDK12-Cyclin K and DDB1, a component of CUL4 E3 ubiquitin ligase complexes, which presents Cyclin K for ubiquitination and degradation. Our results reveal that minor surface-exposed modifications confer gain-of-function glue properties to an inhibitor. We hypothesize that chemical alteration of surface-exposed moieties is a broad strategy to turn a target binder into a molecular glue.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD016187 | Pride | 2020-06-10

REPOSITORIES: pride

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Publications

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation<sup>1</sup>. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets<sup>2</sup>. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations betwe  ...[more]

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