bibf0775

Description: BIBF0775, a 6-substituted indolinone analog, is a novel, potent and selective inhibitor of transforming growth factor beta (TGFbeta) type I receptor (Alk5) with an IC50 of 34 nM. Inhibition of transforming growth factor beta (TGFbeta) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. BIBF0775 was identified as a new chemotype inhibiting TGFbetaRI concomitant with a low cross-reactivity among the human kinome. It also showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRalpha), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFbetaRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. X-ray structure of BIBF0775 indicated that it was soaked into the kinase domain of TGFbetaRI, optimization furnished potent and selective inhibitors of TGFbetaRI. Potent inhibition translated well into good inhibition of TGFbetaRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting.

References: J Med Chem. 2010 Oct 28; 53(20):7287-95.