Discovery of a 2,4-Disubstituted Pyrrolo[1,2-f][1,2,4]triazine Inhibitor (BMS-754807) of Insulin-like Growth Factor Receptor (IGF-1R) Kinase in Clinical Development

Abstract

This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.

Application of Group-Based QSAR and Molecular Docking in the Design of Insulin-Like Growth Factor Antagonists

“…A dataset of 164 IGF-1R inhibitors with their IC 50 values were collected from a Binding-DB database [8,12,13]. The biological activity values (IC 50 ) were converted into the negative logarithmic pIC (-logIC 50 +6).…”

“…The coordinate of 3I81 crystal structure was obtained from the RCSB Data Bank (PDB) [8] and prepared using Protein Preparation Wizard, which is a part of the Maestro software package (Maestro, v9.3, Schrodinger, LLC, New York, NY, 2012). Briefly, all formal charges and bond orders were added for heteroatoms.…”

“…IGF-1R has been widely targeted to decrease cellular proliferation and promote apoptosis in cancers [4,5]. Crystallographic structures of IGF-1R cocrystallized with various ligands have been identified [3,[6][7][8]. The biological activity of these ligands depends on the interactions with certain residues in the ATP binding sites of IGF-1R kinase domain, which serve as hydrogen bond donors, acceptors, or hydrophobic pockets.…”

A Highly Selective Dual Insulin Receptor (IR)/Insulin-like Growth Factor 1 Receptor (IGF-1R) Inhibitor Derived from an Extracellular Signal-regulated Kinase (ERK) Inhibitor

“…To assess the selectivity of Irfin1 as compared with that of BMS-754807 (40,42) and OSI-906/linsitinib (43), two IR/IGF-1R inhibitors in clinical development, we screened each inhibitor against a panel of ϳ300 protein kinases using the Reaction Biology Corporation Kinase HotSpot platform (Fig. 5A).…”

“…It is not surprising that OSI-906 inhibits both unphosphorylated and fully-phosphorylated IR/IGF-1R kinases as a close relative of OSI-906, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), binds to an intermediate conformation of the kinase domain where the activation loop is extended, reminiscent of the active state, and where the C helix is in a conformation reminiscent of the inactive state (41,43). However, it was somewhat surprising that BMS-754807 inhibits fully phosphorylated IGF-1R because BMS-754807 was crystallized in complex with unphosphorylated IGF-1R (40). The inhibition of fully phosphorylated IGF-1R can be rationalized by the fact that the conformation of BMS-754807 bound to unphosphorylated IGF-1R (40) can be docked into the structure of the active form of IGF-1R without any clashes (data not shown).…”