Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDCFR kinases

被引：49

作者：

Manley, PW ^{[1
]}

Breitenstein, W ^{[1
]}

Brüggen, J ^{[1
]}

Cowan-Jacob, SW ^{[1
]}

Furet, P ^{[1
]}

Mestan, J ^{[1
]}

Meyer, T ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 23期

关键词：

Gleevec; tyrosine kinase;

D O I：

10.1016/j.bmcl.2004.09.042

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent ST1571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC50 value of 56nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards AN and 23 selective for PDGFR. (C) 2004 Elsevier Ltd. All rights reserved.

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收藏

页码：5793 / 5797

页数：5

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