Katayama Katsushi, Ishii Ken, Terashima Hideki, Tsuda Eisuke, Suzuki Makoto, Yotsumoto Keiichi, Hiramoto Kumiko, Yasumatsu Isao, Torihata Munefumi, Ishiyama Takashi, Muto Tsuyoshi, Katagiri Takahiro
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
ACS Med Chem Lett. 2020 Dec 28;12(1):121-128. doi: 10.1021/acsmedchemlett.0c00572. eCollection 2021 Jan 14.
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.
通过治疗性激活γ-珠蛋白基因来产生胎儿血红蛋白（HbF）是治疗β地中海贫血和镰状细胞病的一种有吸引力的策略。据报道，组蛋白赖氨酸甲基转移酶EHMT2/1（G9a/GLP）的基因敲低足以诱导HbF的产生。本研究的目的是获得一种能充分诱导HbF产生的G9a/GLP抑制剂。结果表明，四氢氮杂卓在各种骨架中作为侧链具有通用性。我们最终获得了一种有前景的氨基吲哚衍生物（DS79932728），一种强效且口服生物可利用的G9a/GLP抑制剂，该抑制剂在放血的食蟹猴模型中被发现可诱导γ-珠蛋白的产生。这项工作有助于开发治疗β地中海贫血和镰状细胞病的有效新方法。
