Open AccessOptimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors
Author(s) -
Owen A. Davis,
Kwai-Ming J. Cheung,
Alfie Brennan,
Matthew G. Lloyd,
Matthew J. Rodrigues,
Olivier A. Pierrat,
Gavin W. Collie,
YannVaï Le Bihan,
Rosemary Huckvale,
Alice C. Harnden,
Ana Varela,
Michael D. Bright,
Paul D. Eve,
Angela Hayes,
Alan T. Henley,
Michael D. Carter,
Craig McAndrew,
Rachel Talbot,
Rosemary Burke,
Rob L. M. van Montfort,
Florence I. Raynaud,
Olivia W. Rossanese,
Mirco Meniconi,
Benjamin R. Bellenie,
Swen Hoelder
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c02174
Subject(s) - chemistry , complementarity (molecular biology) , bcl6 , tricyclic , stereochemistry , chemical space , combinatorial chemistry , small molecule , drug discovery , biochemistry , b cell , germinal center , genetics , antibody , immunology , biology
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.
Accelerating Research
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom
Address
John Eccles HouseRobert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom