More than three-quarters of all human proteins are beyond the reach of small molecule developers – at least with traditional (antagonistic/agonistic) pharmacologic approaches. An alternative involves using small molecule “degraders” to destabilize undruggable disease-causing proteins. But, so far, the field has lacked rational strategies for discovering these drugs, relying instead on serendipity.
But now, researchers – mainly from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences – have identified mutations in a gene called UBE2M that cause resistance to all known “glue degraders,” a seemingly rare degrader subset. “We surmised that we could find novel glue degraders by screening compounds with unknown mechanisms of action in these cells,” says Georg Winter, corresponding author of a new paper setting out how to rationally discover molecular glue degraders (1).
How do these degraders work? The compounds redirect E3 ubiquitin ligases toward proteins, which are earmarked for destruction via a process called “ubiquitination” and then degraded by the proteasome. To screen for novel glue degraders, the team engineered cells impaired in E3 activity (“hyponeddylated”). By comparing hyponeddylated cells with E3-proficient cells, the team identified compounds that depend on active E3s – potential molecular glue degraders.
“We were most excited when we identified novel chemical matter that acts via undescribed mechanisms,” says Winter. These compounds were found to induce degradation of the cyclin K protein, which is essential in many different cancer types. Because the molecular mechanism was hitherto unknown, it has yet to be explored therapeutically. “We were surprised to find that our new compounds can degrade CCNK in the absence of a dedicated substrate receptor – a component of cullin–RING ligases,” says Winter.
The researchers are confident that the approach can be scaled – so much so that they’ve founded a new spinout called Proxygen, dedicated to the scalable discovery of novel glue degraders.
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References
- C Mayor-Ruiz et al., “Rational discovery of molecular glue degraders via scalable chemical profiling” (2020). Available at: https://go.nature.com/3ibB3hw.
