Cereblon modulators (CELMoDs) bind to the surface of cereblon to form a ‘hotspot’ for protein-protein interactions. This binding event triggers the recruitment of proteins to the CRL4 E3 ubiquitin ligase complex where they can be ubiquitinated and subsequently degraded. Through this mechanism, low molecular weight CELMoDs (&lt;300 Da) such as lenalidomide can cause the degradation of the zinc finger transcription factors Ikaros and Aiolos. A search for cereblon modulators that degrade new proteins lead to the discovery of CC-885, which exhibits potent antiproliferative activity against a panel of tumor cell lines. We found that the potent anti-cancer activity of CC-885 is caused by the degradation of the protein translation factor G1 to S phase transition 1 (GSPT1). The principal molecular feature on GSPT1 that binds to cereblon is a beta-hairpin incorporating a glycine residue that docks against CC-885. Homology modeling indicated that a similar molecular feature mediates Ikaros recruitment, even though there is no common structural fold or sequence homology other than the key glycine residue. This molecular feature, or ‘degron’, can be found in other proteins including families that had been generally considered undruggable or even unligandable. Looking for this degron in other proteins enabled us to show that the embryonic transcription factor SALL4 is degraded by thalidomide, providing a plausible molecular explanation for the thalidomide birth defect tragedy of the 1950s.

New activities for cereblon modulators: Low molecular weight inducers of targeted protein degradation

2019 Fall National Meeting

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