9DBP

Crystal structure of the LSD1/CoREST histone demethylase in complex with the cofactor FAD and the inhibitor GSK690

これはPDB形式変換不可エントリーです。

9DBP の概要

• エントリーDOI: 10.2210/pdb9dbp/pdb
• 分子名称: Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (6 entities in total)
• 機能のキーワード: lsd1-corest, histone methyltransferase inhibitor, gene regulation
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 89445.70

構造登録者

An, S.,Engel, J.,Wang, Y.,Yu, L.,Cho, U.S. (登録日: 2024-08-23, 公開日: 2025-09-17)

主引用文献

Wang, Y.,Yu, L.,Deng, K.,Packiarajan, M.,Aguilar, A.,An, S.,Liu, X.,Myers, G.,Oh, H.,Singh, S.A.,Cho, U.S.,Wang, S.,Guan, Y.,White, A.D.,Khoriaty, R.,Engel, J.D.
Novel, potent, and orally bioavailable LSD1 inhibitors induce fetal hemoglobin synthesis in a sickle cell disease mouse model.
Blood, 146:356-368, 2025

PubMed Abstract: Small molecules that inhibit LSD1 (lysine-specific demethylase 1, KDM1A) have been shown to induce abundant fetal hemoglobin (HbF) levels in red blood cells both in vitro and in vivo, therefore potentially serving as potent and cost-effective therapeutics to treat the β-globinopathies, sickle cell disease (SCD), and β-thalassemia major (TM). However, most LSD1 inhibitors (LSD1is) that induce HbF in vivo are covalent and irreversible, which leads to adverse effects. In this study, we utilized structure-aided drug design to develop potent new reversible LSD1is, leading to robust γ-globin expression in vitro. Moreover, in a mouse model of SCD, oral administration of these novel inhibitors leads to significant HbF elevation and alleviation of multiple features of disease pathology that are the usual consequences of SCD. In addition, we discovered that combined treatment of an LSD1i with a BRD4 degrader (BD-9136) represses the induction of RUNX1 and PU.1, thereby rescuing the erythroid to myeloid lineage conversion that accompanies LSD1is in hematopoiesis. The data indicate that this new generation of LSD1is can effectively induce HbF levels, reduce SCD pathologies, and are well tolerated by oral administration in SCD mice. We anticipate that the combination of these or related binary compounds offer exciting new therapeutic possibilities for treating SCD and TM.

PubMed: 40332031
DOI: 10.1182/blood.2024028006

実験手法

X-RAY DIFFRACTION (2.66 Å)