BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Joan M Carboni,Francis Lee,Glenn H Cantor,Carolyn Cao,Stephen Hillerman,Marco M Gottardis,Ricardo M Attar,Cliff Chen,Aixin Li,Mark Wittman,Krista Menard,Warren Hurlburt,Zheng Yang,George Trainor,Janet Dell-John,Robert Kramer,Ann Greer,Lorell Discenza,Dolatrai Vyas

doi:10.1158/1535-7163.mct-09-0499

Joan M Carboni, Francis Lee + Show 17 more

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https://doi.org/10.1158/1535-7163.mct-09-0499

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Abstract

BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.

Highlights

Type I insulin-like growth factor-I receptor (IGF-1R) is a transmembrane tyrosine kinase growth factor receptor that plays an essential role in the establishment and maintenance of the transformed phenotype; activation results in mitogenesis and survival for cancer cells [1,2,3,4]
Hyperglycemia was among the observed toxicities of IGF-1R antibody treatment [18]
Due to the high homology of IGF-1R and insulin receptor (IR), many of the antagonists being developed are mAbs that offer the possibility of selectively targeting IGF-1R and avoiding inhibition of IR signaling, which could lead to dysregulation of glucose homeostasis

Summary

Introduction

Type I insulin-like growth factor-I receptor (IGF-1R) is a transmembrane tyrosine kinase growth factor receptor that plays an essential role in the establishment and maintenance of the transformed phenotype; activation results in mitogenesis and survival for cancer cells [1,2,3,4]. IGF-1 and IGF-II to IGF-1R, initiates a cascade of events that leads to activation of downstream signal transduction pathways, primarily the mitogenic signaling pathway mitogen-activated protein kinase (MAPK), and the antiapoptotic/survival pathway IGF-1R is closely related to the insulin receptor (IR). In spite of their structural similarities, activation of IGF-1R leads to cell proliferation, motility, and metastasis, whereas the actions of insulin on IR are directed primarily at regulation of glucose homeostasis. The binding affinities vary, ligands directed to IR and IGF-1R cross-react [10, 11]

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