BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR
BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR
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DOI：
10.1158/1535-7163.mct-09-0499
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发表时间：
2009-12-01
影响因子：
5.7
通讯作者：
Gottardis, Marco M.
中科院分区：
文献类型：
--
作者：
Carboni, Joan M.;Wittman, Mark;Gottardis, Marco M.
BMS-754807是胰岛素样生长因子1受体/胰岛素受体家族激酶（Ki，< 2 nmol/L）的强效可逆抑制剂。它目前正处于I期开发，用于治疗各种人类癌症。BMS-754807在体外可有效抑制多种人类肿瘤类型的生长，包括间充质细胞（尤文氏瘤、横纹肌肉瘤、神经母细胞瘤和脂肪肉瘤），上皮（乳腺、肺、胰腺、结肠、胃）和造血（多发性骨髓瘤和白血病）肿瘤细胞系（IC_（50），5-365 nmol/L）;该化合物引起人横纹肌肉瘤细胞系Rh 41的细胞凋亡，如亚G（1）级分的积累所示，以及通过增加聚ADP核糖聚合酶和半胱天冬酶3裂解。BMS-754807在多种（上皮、间充质和造血）异种移植肿瘤模型中具有体内活性，肿瘤生长抑制范围为53%-115%，最低有效剂量低至6.25 mg/kg，每日经口给药。已在多种人类肿瘤细胞类型中进行了BMS-754807的联合研究，并在与细胞毒性、激素和靶向药物联合时显示出体外协同作用（联合指数，< 1.0）。西妥昔单抗和BMS-754807在体内以多个剂量水平联合使用，导致临床结局优于单药治疗。这些数据表明，BMS-754807是一种有效的口服活性生长因子1受体/胰岛素受体家族靶向激酶抑制剂，可与多种已确立的抗癌药物联合作用。[Mol Cancer Ther 2009;8（12）：3341-9]
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-G(1) 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. [Mol Cancer Ther 2009;8(12):3341-9]