6TEL

Crystal structure of Dot1L in complex with an inhibitor (compound 10).

6TEL の概要

• エントリーDOI: 10.2210/pdb6tel/pdb
• 関連するPDBエントリー: 6TE6
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, ~{N}1-[(~{S})-[2,2-bis(fluoranyl)-1,3-benzodioxol-4-yl]-(3-chloranylpyridin-2-yl)methyl]-~{N}2-(4-methoxy-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-methylsulfonyl-benzene-1,2-diamine, POTASSIUM ION, ... (4 entities in total)
• 機能のキーワード: dot1l, complex structure, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78274.44

構造登録者

Scheufler, C.,Stauffer, F.,Be, C.,Moebitz, H. (登録日: 2019-11-12, 公開日: 2019-12-11, 最終更新日: 2024-01-24)

主引用文献

Stauffer, F.,Weiss, A.,Scheufler, C.,Mobitz, H.,Ragot, C.,Beyer, K.S.,Calkins, K.,Guthy, D.,Kiffe, M.,Van Eerdenbrugh, B.,Tiedt, R.,Gaul, C.
New Potent DOT1L Inhibitors forin VivoEvaluation in Mouse.
Acs Med.Chem.Lett., 10:1655-1660, 2019

PubMed Abstract: In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

PubMed: 31857842
DOI: 10.1021/acsmedchemlett.9b00452

実験手法

X-RAY DIFFRACTION (2.19 Å)