Scientists at Scripps Research have uncovered a critical feature that a promising new class of cancer drugs, known as CELMoDs, needs to be effective.
CELMoDs are designed to attack cancer in a novel way, by binding to a regulatory protein called cereblon, which then triggers the degradation of key cancer-driving proteins. In the study, reported on November 3 in Science, researchers discovered that these drugs, in order to work, need to cause a critical shape-change in cereblon when they bind to it. The finding enables researchers to reliably design effective CELMoDs.
“There are a lot of research groups that have spent considerable time making drugs that bind very tightly to cereblon, but have then scratched their heads in puzzlement that these drugs fail to work,” says study senior author Gabriel Lander, PhD, professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The study’s first author was Randy Watson, PhD, a postdoctoral researcher in the Lander lab.
Cereblon works as part of a major protein-disposal system in cells. This system tags targeted proteins with molecules called ubiquitin, which mark the proteins for destruction by roving protein-breaking complexes known as proteasomes. The ubiquitin-proteasome system is used not only to destroy abnormal or damaged proteins, but also to help regulate the levels of some normal proteins. Cereblon is one of hundreds of “adaptors” used by the ubiquitin-proteasome system to guide the ubiquitin-tagging process towards specific sets of target proteins.
Scientists now recognize that some cancer drugs, including the best-selling myeloma drug lenalidomide (Revlimid), happen to work by binding to cereblon. They do so in a way that forces the ubiquitin-tagging, and consequent destruction, of key proteins that promote cell division — proteins that couldn’t be targeted easily with traditional drugs. Inspired in part by that recognition, drug companies have begun developing cereblon-binding drugs — CELMoDs, also called protein-degradation drugs — that will work even better against myeloma and other cancers.
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