![]() ![]() ![]() “There’s just a lot of things that have to line up, a lot of stars that have to line up, to really get efficient degradation,” says Gray. Even when this happens, ubiquitination doesn’t always induce target degradation. The various surfaces must first come together in a ternary complex, and that interaction must then trigger ubiquitination. It’s not enough for PROTACs just to bring E3s close to target proteins for these drugs to work. “The field just exploded,” says Crews.īut drug companies have quickly run into problems. That knowledge conferred instant clinical validation on cereblon-hijacking PROTACs. These papers electrified the field, because cereblon recruitment for selective target degradation had recently been identified as the mechanism of the immunomodulatory imide (‘IMiD’) drugs, thalidomide and its derivatives, including Celgene’s commercial blockbuster lenalidomide, which is indicated for multiple myeloma. Oncologist Jay Bradner, then at the Dana Farber Cancer Institute (and currently president of the Novartis Institute for Biomedical Research), and his group also reported a selective and effective cereblon-recruiting PROTAC. That year, Crews and colleagues reported small-molecule PROTACs with nanomolar potency that behaved catalytically, as well as PROTACs that recruited the cereblon E3 ligase. But it’s still too early to predict that level of success.”īecause the original approach employed bulky peptide E3 ligands, PROTACs remained an innovative idea without much practical application or commercial interest until 2015. And if it is successful, then I think the sector could grow like biologics grew after some of the original Genentech antibodies, become a general modality. ![]() “People want to see clinical successes, to reinvest in that area. “The next couple of years will be pivotal,” says Stanford organic chemist Nathanael Gray, a co-founder of PROTAC company C4 Therapeutics. They’re harder to develop than traditional small molecules, they don’t easily degrade many types of protein, their toxicology is uncertain and side effects are largely unknown. As experience with PROTACs has grown, limitations have begun to emerge. ![]() But it’s not yet a slam-dunk that they will mature into a major new drug modality. By harnessing the cell’s own disposal system to degrade proteins of choice, PROTACs can eliminate otherwise undruggable disease-causing proteins, as well as overcome resistance to conventional small molecules. The potential of this approach is enormous. ![]()
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June 2023
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