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Bioorg Med Chem. 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.

Author information

1
Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takeshi.yasui@takeda.com.
2
Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
3
Takeda California Inc., 10410 Science Center Dr., San Diego, CA 92121, USA.
4
Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yasuhiro.imaeda@takeda.com.

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)

PMID:
28760529
DOI:
10.1016/j.bmc.2017.07.037
[Indexed for MEDLINE]

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