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

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.

SUBMITTER: Katayama K 

PROVIDER: S-EPMC7812670 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Katayama Katsushi K   Ishii Ken K   Terashima Hideki H   Tsuda Eisuke E   Suzuki Makoto M   Yotsumoto Keiichi K   Hiramoto Kumiko K   Yasumatsu Isao I   Torihata Munefumi M   Ishiyama Takashi T   Muto Tsuyoshi T   Katagiri Takahiro T  

ACS medicinal chemistry letters 20201228 1

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  ...[more]

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