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ICR scientists reveal new ways to convert inhibitor-style targeted cancer drugs into degraders

ICR scientists reveal new ways to convert inhibitor-style targeted cancer drugs into degraders

Researchers from the Institute of Cancer Research (ICR) have discovered a new way to convert inhibitor-style targeted cancer drugs into degraders, small molecules, to destroy cancer-promoting proteins in cells. Findings from the study could help researchers create more effective treatments for cancer

Published in ACS Chemical Biology, scientists could use this novel approach to replicate and optimise a range of protein degraders for more effective new cancer treatments.

In cancer treatment, protein kinase inhibitors work to block the action of protein kinases, enzymes that control the function of proteins and can lead to cell growth if they become mutated. However, for some patients, this treatment can pose a risk of the cancer becoming resistant to it.

This study offers the potential of designing molecular glues to identify promising targets for degradation and developing molecules that can function as degrader therapies to completely eradicate these proteins and overcome resistance.

With the aim of understanding the structure-activity relationship of molecular glues, researchers used a known monovalent degrader called CR8 and tried to replace the pyridine in it with a range of substitutes. CR8 inhibits all cyclin-dependant kinases (CDK) which play multiple roles in the development of tumours, while also degrading the cyclin K protein, which promotes cancer signalling pathways.

Previous research has also shown that CR8 binds to CDK12 and an E3 ligase component known as damaged DNA binding protein 1, which allows the cell to break down cyclin K bound to CDK12. Researchers first used simple groups, including fluorine, methyl and hydroxy, and later used more complex formations to determine how these changes affected degradation ability.

The team then applied degrader SAR to other CDK-inhibitors and found that molecular components that induced protein degradation could convert multiple different inhibitors into degraders.

Additionally, they identified substitutes that improved degradation ability.

Dr Benjamin Bellenie, senior staff scientist, ICR’s Division of Cancer Therapeutics, commented: “This study has significantly improved our understanding around the design of monovalent degraders.

“Our team is currently exploring whether certain groups can be joined to other types of kinase inhibitors to turn them into monovalent degraders. Work is also underway to determine whether these compounds can degrade other proteins,” added ICR’s Division of Cancer Therapeutics PhD student, Katie Thomas.

April 17, 2024

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