New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms

被引：24

作者：

Spurr, Sophie S. ^{[1
]}

Bayle, Elliott D. ^{[1
]}

Yu, Wenyu ^{[2
]}

Li, Fengling ^{[2
]}

Tempel, Wolfram ^{[2
]}

Vedadi, Masoud ^{[2
,3
]}

Schapira, Matthieu ^{[2
,3
]}

Fish, Paul V. ^{[1
,4
]}

机构：

[1] UCL, UCL Sch Pharm, 29-39 Brunswick Sq, London WC1N 1AX, England

[2] Univ Toronto, Struct Genom Consortium, MaRS Ctr, 101 Coll St,South Tower, Toronto, ON MG5 1L7, Canada

[3] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[4] UCL, Alzheimers Res UK UCL Drug Discovery Inst, Gower St, London WC1E 6BT, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 18期

基金：

巴西圣保罗研究基金会; 英国惠康基金; 加拿大创新基金会;

关键词：

Protein methyltransferase; DOT1L inhibitors; Toyocamycin; Bioisostere; Cyano-deaza-SAH; H3K79; METHYLATION; POTENT; LEUKEMIA; DERIVATIVES; TOYOCAMYCIN;

D O I：

10.1016/j.bmcl.2016.07.041

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4518 / 4522

页数：5

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