6TUY

Human LSD1/CoREST bound to the quinazoline inhibitor MC4106

6TUY の概要

• エントリーDOI: 10.2210/pdb6tuy/pdb
• 分子名称: Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (9 entities in total)
• 機能のキーワード: epigenetics, histone demethylase, epigenetic inhibitor, dual inhibitor, oxidoreductase
• 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: 149324.00

構造登録者

Mattevi, A.,Marrocco, B. (登録日: 2020-01-08, 公開日: 2021-07-21, 最終更新日: 2024-01-24)

主引用文献

Menna, M.,Fiorentino, F.,Marrocco, B.,Lucidi, A.,Tomassi, S.,Cilli, D.,Romanenghi, M.,Cassandri, M.,Pomella, S.,Pezzella, M.,Del Bufalo, D.,Zeya Ansari, M.S.,Tomasevic, N.,Mladenovic, M.,Viviano, M.,Sbardella, G.,Rota, R.,Trisciuoglio, D.,Minucci, S.,Mattevi, A.,Rotili, D.,Mai, A.
Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models.
Eur.J.Med.Chem., 237:114410-114410, 2022

PubMed Abstract: LSD1 is a histone lysine demethylase proposed as therapeutic target in cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2-4 and 6-30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 μM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone mark H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC range, highlighting a crucial anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines.

PubMed: 35525212
DOI: 10.1016/j.ejmech.2022.114410

実験手法

X-RAY DIFFRACTION (2.6 Å)