Saltar al contenido
Merck
  • Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors.

Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors.

Journal of medicinal chemistry (2017-05-10)
William McCoull, Roman D Abrams, Erica Anderson, Kevin Blades, Peter Barton, Matthew Box, Jonathan Burgess, Kate Byth, Qing Cao, Claudio Chuaqui, Rodrigo J Carbajo, Tony Cheung, Erin Code, Andrew D Ferguson, Shaun Fillery, Nathan O Fuller, Eric Gangl, Ning Gao, Matthew Grist, David Hargreaves, Martin R Howard, Jun Hu, Paul D Kemmitt, Jennifer E Nelson, Nichole O'Connell, D Bryan Prince, Piotr Raubo, Philip B Rawlins, Graeme R Robb, Junjie Shi, Michael J Waring, David Whittaker, Marta Wylot, Xiahui Zhu
RESUMEN

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 100000-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 antiproliferative 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.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
FX1, ≥98% (HPLC)