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Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

ABSTRACT: To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

SUBMITTER: Davis OA

PROVIDER: S-EPMC9234963 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

Davis Owen A OA Cheung Kwai-Ming J KJ Brennan Alfie A Lloyd Matthew G MG Rodrigues Matthew J MJ Pierrat Olivier A OA Collie Gavin W GW Le Bihan Yann-Vaï YV Huckvale Rosemary R Harnden Alice C AC Varela Ana A Bright Michael D MD Eve Paul P Hayes Angela A Henley Alan T AT Carter Michael D MD McAndrew P Craig PC Talbot Rachel R Burke Rosemary R van Montfort Rob L M RLM Raynaud Florence I FI Rossanese Olivia W OW Meniconi Mirco M Bellenie Benjamin R BR Hoelder Swen S

Journal of medicinal chemistry 20220603 12

To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray st ...[more]

PMID: 35657291

Dataset Information

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

Publications

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

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