The surprising versatility of MGDs: Different ways for Cereblon to engage its targets

Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4–RING E3 ubiquitin ligase (CRL4^CRBN), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras–GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein–protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, glueprints’) could become a viable strategy for the rational expansion of the MGD target repertoire. In this webinar, we will share the journey of elucidating the G3BP2 binding mode with the CRBN–MGD complex through a multifaceted approach showcasing the capabilities of our QUEEN™ platform - the drug discovery engine at Monte Rosa Therapeutics - including a special focus on our structural biology workflow for cryo-electron microscopy (cryo-EM) structure determination. 

We will explore:

• Molecular glue degraders (MGDs) as a novel therapeutic approach for challenging drug targets
• Integrated approaches of our QUEEN™ platform to enable the rational discovery of novel binding modes
• Spotlight on our cryo-EM pipeline: including elucidating ternary complex interfaces, coping with conformational heterogeneity and other examples