Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.

ABSTRACT: We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition

SUBMITTER: Lloyd MG 

PROVIDER: S-EPMC8667045 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature