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

Joan M Carboni1, Mark Wittman, Zheng Yang

  • 1Oncology Drug Discovery, Department of Pharmaceutical Candidate Organization, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA. joan.carboni@bms.com

Molecular Cancer Therapeutics
|December 10, 2009
PubMed

Insights

BMS-754807, a novel kinase inhibitor, effectively targets cancer cell growth across various types. It shows promise as an oral treatment, both alone and in combination with other therapies, for diverse human cancers.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • The insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) family kinases play crucial roles in cell growth and cancer progression.
  • Targeting these kinases presents a potential therapeutic strategy for various human cancers.

Purpose of the Study:

  • To evaluate the efficacy of BMS-754807, a potent inhibitor of IGF-1R/IR family kinases, as a potential anticancer agent.
  • To assess the in vitro and in vivo activity of BMS-754807 against a broad spectrum of human tumor types.
  • To investigate the synergistic potential of BMS-754807 in combination with other anticancer agents.

Main Methods:

  • In vitro kinase inhibition assays to determine the potency of BMS-754807.
  • Cell viability assays across diverse human cancer cell lines (mesenchymal, epithelial, hematopoietic) to assess IC50 values.
  • Apoptosis assays (sub-G1 fraction, PARP and Caspase 3 cleavage) in a human rhabdomyosarcoma cell line.
  • In vivo efficacy studies using xenograft tumor models in mice.
  • In vitro and in vivo combination studies with cytotoxic, hormonal, and targeted agents, including cetuximab.

Main Results:

  • BMS-754807 demonstrated potent and reversible inhibition of IGF-1R/IR family kinases (Ki < 2 nmol/L).
  • The compound effectively inhibited the growth of a wide range of human tumor cell lines in vitro (IC50: 5-365 nmol/L) and induced apoptosis in rhabdomyosarcoma cells.
  • BMS-754807 showed significant in vivo tumor growth inhibition (53%-115%) in multiple xenograft models at low oral doses (≥6.25 mg/kg/day).
  • Synergistic effects (combination index < 1.0) were observed in vitro when BMS-754807 was combined with various anticancer agents.
  • Combination therapy with cetuximab demonstrated improved clinical outcomes in vivo compared to single-agent treatment.

Conclusions:

  • BMS-754807 is an effective, orally active kinase inhibitor targeting the IGF-1R/IR family.
  • The compound exhibits broad-spectrum anticancer activity in vitro and in vivo.
  • BMS-754807 shows significant potential for combination therapy with established anticancer agents, offering a promising strategy for cancer treatment.

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