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Aug 04, 2016
 |  BC Innovations  |  Targets & Mechanisms

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 of action to work backwards and find more substrates that can be degraded by the imid family (see Figure: Good riddance to new rubbish).

In a Naturestudy published in June, the company identified an imid that promoted degradation of GSTP1, a translation termination factor. Through structural analysis, the authors found a hairpin-shaped motif in GSTP1 that was critical for its recruitment to cereblon.

The team showed the structural feature, dubbed a "degron," is also present in IKAROS and the kinase CSNK1A - which was also recently identified as a substrate for imid-induced degradation. According to Vessey, that means the motif could be used to find new proteins that can be similarly captured by imids.

"There may be some structural determinants of proteins that indicate whether they may be substrates for cereblon-modulating drugs, and based on that, there are a lot of potential substrates," Vessey said. "What that means is going forward, you might be able to more deliberately design compounds that bind to and modulate cereblon function, and be more deliberate about the substrates that you want to degrade."

He noted the results are "the beginning of an extremely...

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