2X7O

Crystal structure of TGFbRI complexed with an indolinone inhibitor

Summary for 2X7O

• Entry DOI: 10.2210/pdb2x7o/pdb
• Related: 1B6C 1IAS 1PY5 1RW8 1VJY 2WOT 2WOU
• Descriptor: TGF-BETA RECEPTOR TYPE I, (3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE (2 entities in total)
• Functional Keywords: kinase, transferase, glycoprotein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 5
• Total formula weight: 197076.34

Authors

Roth, G.J.,Heckel, A.,Brandl, T.,Grauert, M.,Hoerer, S.,Kley, J.T.,Schnapp, G.,Baum, P.,Mennerich, D.,Schnapp, A.,Park, J.E. (deposition date: 2010-03-03, release date: 2010-10-20, Last modification date: 2023-12-20)

Primary citation

Roth, G.J.,Heckel, A.,Brandl, T.,Grauert, M.,Hoerer, S.,Kley, J.T.,Schnapp, G.,Baum, P.,Mennerich, D.,Schnapp, A.,Park, J.E.
Design, Synthesis and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor Beta Receptor I (Tgfbri)
J.Med.Chem., 53:7287-, 2010

PubMed Abstract: 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.

PubMed: 20919678
DOI: 10.1021/JM100812A

Experimental method

X-RAY DIFFRACTION (3.7 Å)