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Discovery of pyrazolo[1,5-a]pyrimidine B-cell lymphoma 6 (BCL6) binders and optimization to high affinity macrocyclic inhibitors

Lookup NU author(s): Professor Mike Waring



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2017.

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Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure based drug design, binding affinity was increased 100,000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak anti-proliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

Publication metadata

Author(s): McCoull W, Abrams RD, Anderson E, Blades K, Barton P, Box M, Burgess J, Byth K, Cao Q, Chuaqui C, Carbajo RJ, Cheung T, Code E, Ferguson AD, Fillery S, Fuller NO, Gangl E, Gao N, Grist M, Hargreaves D, Howard MR, Hu J, Kemmitt PD, Nelson JE, OConnell N, Prince DB, Raubo P, Rawlins PB, Robb GR, Shi J, Waring MJ, Whittaker D, Wylot M, Zhu X

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2017

Volume: 60

Issue: 10

Pages: 4386-4402

Print publication date: 25/05/2017

Online publication date: 09/05/2017

Acceptance date: 08/05/2017

Date deposited: 09/05/2017

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.7b00359


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