Discovery of Reversible Inhibitors of KDM1A Efficacious in Acute Myeloid Leukemia Models

被引：22

作者：

Romussi, Alessia ^{[1
]}

Cappa, Anna ^{[1
]}

Vianello, Paola ^{[1
]}

Brambillasca, Silvia ^{[1
]}

Cera, Maria Rosaria ^{[1
]}

Dal Zuffo, Roberto ^{[1
]}

Faga, Giovanni ^{[1
]}

Fattori, Raimondo ^{[1
]}

Moretti, Loris ^{[1
]}

Trifiro, Paolo ^{[1
]}

Villa, Manuela ^{[1
]}

Vultaggio, Stefania ^{[1
]}

Cecatiello, Valentina ^{[2
]}

Pasqualato, Sebastiano ^{[2
]}

Dondio, Giulio ^{[3
]}

So, Chi Wai Eric ^{[4
]}

Minucci, Saverio ^{[1
,5
]}

Sartori, Luca ^{[1
]}

Varasi, Mario ^{[1
]}

Mercurio, Ciro ^{[1
]}

机构：

[1] European Inst Oncol IRCCS, Dept Expt Oncol, Acad Drug Discovery, I-20139 Milan, Italy

[2] European Inst Oncol IRCCS, IEO, Dept Expt Oncol, Biochem & Struct Biol Unit, I-20139 Milan, Italy

[3] Aphad Srl, I-20090 Buccinasco, MI, Italy

[4] Kings Coll London, Dept Haematol Med, Div Canc Studies, Leukemia & Stem Cell Biol Grp, London SE5 9NU, England

[5] Univ Milan, Dept Biosci, I-20133 Milan, Italy

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 05期

基金：

英国医学研究理事会;

关键词：

Reversible inhibitors; LSD1; KDM1A; epigenetics; leukemia; lysine-specific demethylase-1; LYSINE; DERIVATIVES; ROLES;

D O I：

10.1021/acsmedchemlett.9b00604

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as a transcription corepressor or coactivator by regulating the methylation status of histone H3 lysines K4 and K9, respectively. KDM1A represents an attractive target for cancer therapy. While, in the past, the main medicinal chemistry strategy toward KDM1A inhibition was based on the optimization of ligands that irreversibly bind the FAD cofactor within the enzyme catalytic site, we and others have also identified reversible inhibitors. Herein we reported the discovery of 5-imidazolylthieno[3,2-b]pyrroles, a new series of KDM1A inhibitors endowed with picomolar inhibitory potency, active in cells and efficacious after oral administration in murine leukemia models.

引用

页码：754 / 759

页数：6

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