A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia

被引：12

作者：

Sellmer, Andreas ^{[1
]}

Pilsl, Bernadette ^{[1
]}

Beyer, Mandy ^{[2
]}

Pongratz, Herwig ^{[1
]}

Wirth, Lukas ^{[1
]}

Elz, Sigurd ^{[1
]}

Dove, Stefan ^{[1
]}

Henninger, Sven Julian ^{[2
]}

Spiekermann, Karsten ^{[3
]}

Polzer, Harald ^{[3
]}

Klaeger, Susan ^{[4
]}

Kuster, Bernhard ^{[4
]}

Boehmer, Frank D. ^{[5
]}

Fiebig, Heinz-Herbert ^{[6
]}

Kraemer, Oliver H. ^{[2
]}

Mahboobi, Siavosh ^{[1
]}

机构：

[1] Univ Regensburg, Fac Chem & Pharm, Inst Pharm, D-93040 Regensburg, Germany

[2] Univ Med Ctr, Dept Toxicol, Mainz, Germany

[3] Ludwig Maximilians Univ Munchen, Dept Med 3, Univ Hosp, Munich, Germany

[4] Tech Univ Munich, Wissenschaftszentrum Weihenstephan Ernahrung Land, Munich, Germany

[5] Univ Klinikum Jena, Bachstr 18, D-07743 Jena, Germany

[6] 4HF Biotec GmbH, Flughafen 14, D-79108 Freiburg, Germany

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 193卷

关键词：

FLT3; FLT3-ITD; D835Y; Tyrosine kinase inhibitor; Acute myeloid leukemia; INTERNAL TANDEM DUPLICATION; THERAPEUTIC TARGET; F691L MUTATION; IN-VITRO; AML; RESISTANCE; CRENOLANIB; POTENT; CELLS; VALIDATION;

D O I：

10.1016/j.ejmech.2020.112232

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD. (c) 2020 Elsevier Masson SAS. All rights reserved.

引用

页数：20

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