DS79932728的发现：一种用于治疗β地中海贫血和镰状细胞病的强效口服G9a/GLP抑制剂。
Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease.
作者信息
Katayama Katsushi, Ishii Ken, Terashima Hideki, Tsuda Eisuke, Suzuki Makoto, Yotsumoto Keiichi, Hiramoto Kumiko, Yasumatsu Isao, Torihata Munefumi, Ishiyama Takashi, Muto Tsuyoshi, Katagiri Takahiro
机构信息
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.
出版信息
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。
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