www.science.org/doi/10.1126/...

Fabulous! Unfortunately, I’ll have to be there in spirit 👕 this year! Hoping to join at the next world tour 🚌 stop.

We anticipate that unbiased phenotypic screening in combination with biased E3-focused small molecule libraries will continue to be a fruitful approach to molecular glue discovery. This amazing work comes from a large team at @amgen.bsky.social in collaboration w/ @PlexiumTx. Congrats to all

SAR analysis provided the opportunity to directly test the impact of altering k-on and k-off rates, which revealed that slow k-off as far more important than fast k-on for degradation activity. 7/8

Comprehensive mutational analysis revealed the GEMIN3 degron by which dGEM3 mediates recognition by VHL. 6/8

We extensively characterize the properties of dGEM3 to show biochemical reconstitution of the VHL:dGEM3:GEMIN3 ternary complex and ubiquitination consistent with a molecular glue without pre-existing affinity between VHL and GEMIN3. 5/7

Proteomics analysis reveals dGEM3 is a highly selective degrader and the direct target is the SMN complex protein GEMIN3. 4/8

We discover dGEM3 as a VHL-based molecular glue causing significant gene expression changes. 3/8

We use an innovative gene expression read out approach to do target-agnostic screening of a focused 26,000 VHL ligand library for molecular glue degraders. 2/8

Thanks to all co-authors on this amazing Amgen-UCBerkeley Molecular Therapeutics Initiative collaboration, especially Charlotte Zammit, Cory Nadel, Ying Lin, and Sajjan Koirala. 7/7

Overall, these results indicated that EN1441 is a pathfinding molecule that directly engages AR-v7 Cys125, leading to destabilization and aggregation and the subsequent inhibition of AR transcriptional activity and ultimately ubiquitin-mediated proteasomal degradation. 6/7