Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor β Receptor I (TGFβRI)
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- 作者：Gerald J. Roth ; Armin Heckel ; Trixi Brandl ; Matthias Grauert ; Stefan Hoerer ; Joerg T. Kley ; Gisela Schnapp ; Patrick Baum ; Detlev Mennerich ; Andreas Schnapp ; John E. Park
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：October 28, 2010
- 年：2010
- 卷：53
- 期：20
- 页码：7287-7295
- 全文大小：939K
- 年卷期：v.53,no.20(October 28, 2010)
- ISSN：1520-4804
文摘
Inhibition of transforming growth factor β (TGFβ) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFβRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRα), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFβRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. Guided by an X-ray structure of lead compound 5 (BIBF0775) soaked into the kinase domain of TGFβRI, optimization furnished potent and selective inhibitors of TGFβRI. Potent inhibition translated well into good inhibition of TGFβRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting. Optimized compounds were extensively profiled on a 232-kinase panel and showed low cross-reactivities within the human kinome.