(1/4) Molecular glue degraders are captivating drug discovery, but how might drug resistance emerge? Read our new preprint! We identify themes of degrader resistance involving neosubstrates. #TPD biorxiv.org/content/10.110… 
(2/4) Using CRISPR-suppressor scanning, we surveyed the resistance landscape across 2 neosubstrates. As expected, the ternary complex interface is a resistance hotspot. But different interfaces can tolerate different amounts of mutations, influencing resistance.
(3/4) When the interface is mutationally constrained, distal mutations can pop up in unexpected places in the neosubstrate. For us, these mutations only partially impact degradation. But small changes in degradation can sometimes lead to big changes in phenotype/resistance.
(4/4) Knowing the resistance landscape to degraders might teach us about aspects of neosubstrates that allow for more effective targeted protein degradation. Big shoutout to @liaulab folks involved, especially @Palgosavi and @lilchromatinboy for leading this effort.
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