2. Academic Validation
  3. Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors

  • J Med Chem. 2022 Jun 23;65(12):8169-8190. doi: 10.1021/acs.jmedchem.1c02174.
Owen A Davis 1,  Kwai-Ming J Cheung 1,  Alfie Brennan 1,  Matthew G Lloyd 1,  Matthew J Rodrigues 1 2,  Olivier A Pierrat 1,  Gavin W Collie 1 2,  Yann-Vaï Le Bihan 1 2,  Rosemary Huckvale 1,  Alice C Harnden 1,  Ana Varela 1,  Michael D Bright 1,  Paul Eve 1,  Angela Hayes 1,  Alan T Henley 1,  Michael D Carter 1,  P Craig McAndrew 1,  Rachel Talbot 1,  Rosemary Burke 1,  Rob L M van Montfort 1 2,  Florence I Raynaud 1,  Olivia W Rossanese 1,  Mirco Meniconi 1,  Benjamin R Bellenie 1,  Swen Hoelder 1
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K..
  • 2 Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K..
PMID: 35657291 DOI: 10.1021/acs.jmedchem.1c02174
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.

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