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A molecular glue that promotes cyclin K degradation
Published on janvier 23, 2024
The CDK12 and cyclin K proteins form a complex that plays important roles in several types of cancer, including melanoma and breast cancer. The team led by Philippe Roux, IRIC’s Scientific Director and Head of its Cell Signaling and Proteomics Research Unit, has characterized the mode of action of a novel CDK12 inhibitor, developed for its therapeutic anticancer potential. The results obtained reveal that the inhibitor in question, the molecule SR-4835, acts as a molecular glue to induce the degradation of cyclin K and thus inactivate the complex it forms with CDK12. Conducted jointly by postdocs Thibault Houles and Jonathan Boucher, the project has been published in the journal Cell Death Discovery.
A molecular glue that recruits a degrader complex
Through a genetic screen carried out in collaboration with Stéphane Angers’ team at the University of Toronto, as well as molecular biology and biochemistry experiments, the team shed light on the mechanism of action enabling SR-4835 to be toxic to cells. The results indeed demonstrated that the inhibitor promotes the interaction of the CDK12 – cyclin K complex with a second complex, whose role is to mediate the destruction of targeted proteins. Thus, SR-4835 binds to CDK12 – cyclin K and recruits a destructive complex which then causes cyclin K degradation.
A molecule that can be chemically optimized
By analyzing the structure of SR-4835, the team identified the portion of the molecule responsible for its molecular glue activity. Modification of this portion generates different SR-4835 derivatives of varying potency. It will therefore be possible, through further experiments, to molecularly optimize SR-4835 to increase its efficacy, and hence its ability to promote cyclin K destruction.
The study carried out by the Roux laboratory has shed light on the mechanism of action of a novel CDK12 inhibitor, and provides new knowledge on which to base the development of molecular glues for anticancer purposes.
Cited study
Houles T, Boucher J, Lavoie G, MacLeod G, Lin S, Angers S, Roux PP. The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma. Cell Death Discov. 9, 459 (2023). https://doi.org/10.1038/s41420-023-01754-x
