BMS-754807 is a potent and small molecular inhibitor which targets the IGF-1R/IR family kinases with Ki <2 nmol/L[1]. The efficacy of BMS-754807 on normal tissues and tumor cell cycle is believed to be different from the effects of continuous inhibition by anti-IGF-1R antibodies.[2]
BMS-754807 could effectively inhibit the growth of many human tumor types from in vitro perspective, such as mesenchymal, hematopoietic and epithelial tumor cell lines with an IC50 value of 5–365 nmol/L. It can also induce sub-G1 fraction accumulation and an increase in poly ADP ribose polymerase and Caspase 3 cleavage, suggesting that it can lead to apoptosis in a human rhabdomyosarcoma cell line (Rh41). Furthermore, as a pyrrolotriazine and reversible ATP-competitive antagonist of IGF-1R, BMS-754807 was shown to inhibit the catalytic domain of the IGF-1R, and proved to inhibit the IGF-1R and IR activity by using the in-vitro kinase assays. Since the antibodies can bind to IGF-1R but not to IR, this could be regardere as an escape mechanism for IGF-II and insulin signaling.[3]
References:
[1] Q.S. Chu，S.W. Kim，P.M. Ellis，L. Mileshkin，R.H. de Boer，J.S. Park，T. Pellas，F(xiàn). Huang，F(xiàn). Graf Finckenstein，A. Dhar. BMS-754807, an oral dual IGF-1R/insulin receptor (IR) inhibitor: initial results from a Phase 1 dose- and schedule-?nding study in combination with carboplatin/paclitaxel in subjects with solid tumors. European Journal of Cancer Supplements. November 2010, 8(7): 131.
[2] Vattoly J. Majo, Victoria Arango, Norman R. Simpson, Jaya Prabhakaran, Suham A. Kassir, Mark D. Underwood, Mihran Bakalian, Peter Canoll, J. John Mann, J.S. Dileep Kumar. Synthesis and in vitro evaluation of [18F]BMS-754807: A potential PET ligand for IGF-1R. Bioorganic & Medicinal Chemistry Letters. July 2013, 23(14): 4191-4194.
[3] Joan M. Carboni, Mark Wittman, Zheng Yang, et al.. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009;8:3341-3349.
