Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders.

ABSTRACT: Targeted protein degradation (TPD) holds immense promise for drug discovery, but mechanisms of acquired resistance to degraders remain to be fully identified. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)-suppressor scanning to identify mechanistic classes of drug resistance mutations to molecular glue degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase substrate receptors cereblon and DCAF15, respectively. While many mutations directly alter the ternary complex heterodimerization surface, distal resistance sites were also identified. Several distal mutations in RBM39 led to modest decreases in degradation, yet can enable cell survival, underscoring how small differences in degradation can lead to resistance. Integrative analysis of resistan

SUBMITTER: Gosavi PM 

PROVIDER: S-EPMC9052798 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature