| |
[摘要]：Inhibition of transforming growth factor beta (TGF beta) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. I ndolinones substituted in position 6 were identified as a new chemotype inhibiting TGF beta RI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFR alpha), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGF beta RI 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 TGF beta RI, optimization furnished potent and selective inhibitors of TGF beta RI. Potent inhibition translated well into good inhibition of TGF beta RI-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. |
|
