Fig. 3: MRT-31619 is a degron-mimicking CRBN molecular glue.
From: A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation
a The cis CRBN (CRBN1) binds one MRT-31619 molecule (MGD1) at the tri-tryptophan pocket and interacts with the trans MRT-31619 molecule (MGD2) via a hydrogen bond to W400. b CRBN W400 interacts with the CK1α G-loop via a hydrogen bond in the presence of lenalidomide. c Superposition of panels a and b indicates that MGD2 is a structural mimic of the CK1α G-loop and employs the same hydrogen bond. d–f Chemical structures of MRT-31619, MRT-31015, or MRT-30568 and their corresponding global quantitative proteomics data in Jurkat cells. Volcano plots show compound/DMSO protein abundance upon treatment with 10 μM of MRT-31619, MRT-31015, or MRT-30568 for 24 h. g HEK293T_HiBiT-CRBN degradation upon MRT-31619, MRT-31015, or MRT-30568 treatment for 1 h. Four biological replicates were plotted as mean ± SD. h NanoBRET assay for HaloTag-CRBN and CRBN-NanoLuc constructs upon MRT-31619, MRT-31015, or MRT-30568 treatment. Three biological replicates were plotted as mean ± SEM. i Flow-induced dispersion analysis (FIDA) for MRT-31619, MRT-31015, or MRT-30568 and the corresponding EC50 and Max Rh values. The predicted value of Rh calculated from the cryo-EM structure of the ternary complex is 7.47 nm. Three biological replicates were plotted as mean ± SD. Source data are provided as a Source Data file.
