title: BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR.
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.
authors.affiliation: Oncology Drug Discovery, Department of Pharmaceutical Candidate Organization, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA. joan.carboni@bms.com
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Mark
authors.initials: M
authors.lastname: Wittman
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Francis
authors.initials: F
authors.lastname: Lee
authors.forename: Ann
authors.initials: A
authors.lastname: Greer
authors.forename: Warren
authors.initials: W
authors.lastname: Hurlburt
authors.forename: Stephen
authors.initials: S
authors.lastname: Hillerman
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cao
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.forename: Janet
authors.initials: J
authors.lastname: Dell-John
authors.forename: Cliff
authors.initials: C
authors.lastname: Chen
authors.forename: Lorell
authors.initials: L
authors.lastname: Discenza
authors.forename: Krista
authors.initials: K
authors.lastname: Menard
authors.forename: Aixin
authors.initials: A
authors.lastname: Li
authors.forename: George
authors.initials: G
authors.lastname: Trainor
authors.forename: Dolatrai
authors.initials: D
authors.lastname: Vyas
authors.forename: Robert
authors.initials: R
authors.lastname: Kramer
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C545990:BMS 754807; D011720:Pyrazoles; D014227:Triazines; D011065:Poly(ADP-ribose) Polymerases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D053148:Caspase 3; D000068818:Cetuximab