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. 2017 Sep 1;25(17):4876-4886.
doi: 10.1016/j.bmc.2017.07.037. Epub 2017 Jul 20.

Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design

Takeshi Yasui  1 , Takeshi Yamamoto  2 , Nozomu Sakai  2 , Kouhei Asano  2 , Takafumi Takai  2 , Yayoi Yoshitomi  2 , Melinda Davis  3 , Terufumi Takagi  2 , Kotaro Sakamoto  2 , Satoshi Sogabe  2 , Yusuke Kamada  2 , Weston Lane  3 , Gyorgy Snell  3 , Masashi Iwata  2 , Masayuki Goto  2 , Hiroshi Inooka  2 , Jun-Ichi Sakamoto  2 , Yoshihisa Nakada  2 , Yasuhiro Imaeda  4
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Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design

Takeshi Yasui et al. Bioorg Med Chem. .

Abstract

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.

Keywords: B cell lymphoma 6 (BCL6); Diphenylamine; Protein–protein interaction (PPI); Structure-based drug design (SBDD).

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