Cereblon ambition

A structural motif could help Celgene find new targets to send to the proteasome

Most anti-cancer strategies aim to block overactive proteins by directly inhibiting their activity, but a growing number of companies are developing ways to tag the proteins for destruction by recruiting the enzymes that shuttle them off to the proteasome. Following the discovery that thalidomide works by that mechanism, Celgene Corp. has used the drug and its analogs to identify a common structural motif, and is using the findings to identify new substrates for degradation.

"The reason people are interested is because you may be able to degrade disease-causing proteins that you can't inhibit by more conventional methods," said Rupert Vessey, Celgene's EVP and president of research and early development. "Often it's because the protein interacts with other proteins through a large interface, and those kinds of interactions are typically hard to inhibit with a small molecule."

In the last six years, Celgene and others have shown that thalidomide and its analogs - known as imids - act by trapping the transcription factors IKAROS and AIOLOS near cereblon, a subunit of E3 ubiquitin ligase, an enzyme that ubiquitinates proteins and marks them for degradation.

But instead of designing new imid-based compounds to target preselected substrates, Celgene is using the mechanism

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