Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease

  • ACS Med Chem Lett. 2020 Dec 28;12(1):121-128. doi: 10.1021/acsmedchemlett.0c00572.
Katsushi Katayama  1 ,  Ken Ishii  1 ,  Hideki Terashima  1 ,  Eisuke Tsuda  1 ,  Makoto Suzuki  2 ,  Keiichi Yotsumoto  1 ,  Kumiko Hiramoto  2 ,  Isao Yasumatsu  3 ,  Munefumi Torihata  1 ,  Takashi Ishiyama  1 ,  Tsuyoshi Muto  1 ,  Takahiro Katagiri  1
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2. Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 3. Daiichi Sankyo RD Novare Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 33488973 DOI: 10.1021/acsmedchemlett.0c00572
Abstract

Therapeutic reactivation of the γ-globin genes for fetal Hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.

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