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

  • Bioorg Med Chem. 2017 Sep 1;25(17):4876-4886. doi: 10.1016/j.bmc.2017.07.037.
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
Affiliations
  • 1. Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
  • 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: [email protected].
PMID: 28760529 DOI: 10.1016/j.bmc.2017.07.037
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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