Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor β Receptor I (TGFβRI)

• Published in: Journal of medicinal chemistry 2010-10, Vol.53 (20), p.7287-7295
• Main Authors: Roth, Gerald J, Heckel, Armin, Brandl, Trixi, Grauert, Matthias, Hoerer, Stefan, Kley, Joerg T, Schnapp, Gisela, Baum, Patrick, Mennerich, Detlev, Schnapp, Andreas, Park, John E
• Format: Article
• Language: English
• Subjects: Cell Line; Crystallography, X-Ray; Drug Design; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Models, Molecular; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; Receptors, Transforming Growth Factor beta - chemistry; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100812a

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.