Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

ABSTRACT: Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule SHD913 exhibited pronounced Brd4 protein degradation with low nM DC₅₀ values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines. Further biological evaluation revealed that the compound exhibited positive cooperativity and induced de novo protein-protein interactions (PPIs) in both biophysical and cellul

SUBMITTER: Li C 

PROVIDER: S-EPMC11672125 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature