Alfred I duPont Hospital for Children, Nemours Center for Childhood Cancer Research, Wilmington, DE, USA.
Pediatr Blood Cancer. 2011 Apr;56(4):595-603. doi: 10.1002/pbc.22741. Epub 2010 Dec 22.
BMS-754807 is a small molecule ATP-competitive inhibitor of the type-1 insulin-like growth factor receptor currently in phase 1 clinical trials.
BMS-754807 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 µM and was tested against the PPTP in vivo panels at a dose of 25 mg/kg administered orally BID for 6 days, repeated for 6 weeks.
In vitro BMS-754807 showed a median EC(50) value of 0.62 µM against the PPTP cell lines. The median EC(50) for the four Ewing sarcoma cell lines was less than that for the remaining PPTP cell lines (0.19 µM vs. 0.78 µM, P = 0.0470). In vivo BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied. Criteria for intermediate activity for the time to event activity measure (EFS T/C > 2) were met in 7 of 27 solid tumor xenografts evaluable for this measure. The best response was PD2 (progressive disease with growth delay), which was observed in 18 of 32 solid tumor xenografts. PD2 responses were most commonly observed in the rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and Wilms tumor panels.
BMS-754807 activity in vitro is consistent with a specific IGF-1R effect that has half-maximal response in the 0.1 µM range and that is observed in a minority of the PPTP cell lines. In vivo intermediate activity was most commonly observed in the neuroblastoma and rhabdomyosarcoma panels.
BMS-754807 是一种小分子 ATP 竞争性抑制剂，可靶向 1 型胰岛素样生长因子受体，目前处于临床 1 期试验阶段。
BMS-754807 在浓度为 1.0 nM 至 10 µM 的范围内，通过儿科临床前测试计划（PPTP）的体外检测板进行了测试，并在剂量为 25 mg/kg 的情况下，通过每天口服两次（BID）的方式，重复给药 6 天，用于测试 PPTP 的体内检测板。
在体外，BMS-754807 对 PPTP 细胞系的中位 EC50 值为 0.62 µM。四种尤因肉瘤细胞系的中位 EC50 值低于其余 PPTP 细胞系（0.19 µM 比 0.78 µM，P = 0.0470）。在体内，与对照组相比，BMS-754807 在 32 个可评估的实体瘤异种移植瘤中的 18 个（56%）中诱导了 EFS 分布的显著差异，但在研究的所有 ALL 异种移植瘤中均未观察到。时间事件活性测量（EFS T/C > 2）的中间活性标准在 27 个可评估该测量的实体瘤异种移植瘤中的 7 个中得到满足。最佳反应是 PD2（伴有生长延迟的进行性疾病），在 32 个可评估的实体瘤异种移植瘤中观察到 18 个。PD2 反应最常见于横纹肌肉瘤、神经母细胞瘤、骨肉瘤、尤因肉瘤和肾母细胞瘤组。
BMS-754807 在体外的活性与其特定的 IGF-1R 效应一致，其半最大反应在 0.1 µM 范围内，并且仅在少数 PPTP 细胞系中观察到。在体内，中间活性最常见于神经母细胞瘤和横纹肌肉瘤组。
