BMS-536924 (BMS 536924) is an ATP-competitive IGF-1R/IR inhibitor with IC50 of 100 nM/73 nM, modest activity for Mek, Fak, and Lck with very little activity for Akt1, MAPK1/2.

Insulin receptor:73 nM, IGF-1R:100 nM

BMS-536924能够以IC50值分别为150 nM和341 nM抑制FAK和Lck。此外，BMS-536924抑制细胞增殖并干扰Akt和MAPK的磷酸化。[1]在MCF10A细胞中，BMS-536924抑制由IGF-I激发的IGF-1R信号传导，并阻断CD8-IGF-1R-MCF10A的IGF-1R固有活性。用1μM BMS-536924预处理MCF10A细胞，能完全阻断IGF-I对IGF-1R磷酸化的激活。IGF-I激发会增加ERK1/2、GSK3β和Akt的磷酸化，BMS-536924抑制这种配体诱导的磷酸化。在CD8-IGF-1R-MCF10A细胞中，BMS-536924处理导致磷酸化的剂量依赖性抑制，0.01 μM和0.1 μM下为部分抑制，1 μM浓度时实现完全受体抑制。在孵育后最早10分钟可观察到IGF-1R磷酸化的最大抑制。BMS-536924保持抑制IGF-1R磷酸化的能力长达48小时。BMS-536924添加后，从1小时开始时间依赖性地抑制Akt磷酸化，并在48小时完全阻断Akt激活。[2] BMS-536924在包括TC32、HT1080/S、SK-LMS-1、H513和CTR细胞系在内的一系列癌细胞系中显示出抗增殖活性。IGF-I/胰岛素刺激导致pIGF-1R/pIR激活，在Rh41和Rh36细胞系中，这种激活被BMS-536924以相似的效力抑制。在用BMS-536924处理的Rh41细胞中，程序性细胞死亡4（PDCD4）、聚(ADP-核糖)聚合酶（PARP）的切割和caspase-3的表达上调。[3]

经口给药BMS-536924以100-300 mpk剂量强烈抑制IGR-1R Sal肿瘤模型。在非转基因Colo205人结肠癌模型中亦观察到疗效。通过每日一次（100-300 mpk）或每日两次（50, 100 mpk）给药方式，展现了对该肿瘤模型的抗肿瘤活性。口服葡萄糖耐量试验（OGTT）显示，100 mpk（b.i.d.）的剂量在葡萄糖挑战后显著升高葡萄糖水平。通过在聚乙二醇400和水（80:20 v/v）中口服给予，测定了BMS-536924在小鼠、大鼠、狗和猴中的药代动力学参数，所有种类中均显示出良好的生物利用度。在啮齿动物中，随着p.o.剂量的增加观察到显著的非线性药代动力学。[1] BMS-536924在两周治疗后（100 mg/kg），将CD8-IGF-1R-MCF10A细胞的瘤体异种移植体体积减小到76%。[2] 70 mg/kg BMS-536924的经口给药显著抑制接种于裸鼠中的TGBC-1TKB细胞的肿瘤生长。BMS-536924上调异种移植瘤中的凋亡。治疗对小鼠的体重或死亡时的葡萄糖水平没有不良影响，表明毒性可容忍。[4]

IGF-I Pathway Activity: 1 × 106 pBabe-MCF10A cells are seeded onto 60-mm dishes. After 24 hours, the medium is changed to serum-free medium and incubated overnight at 37 °C for 24 hours. Cells are then pre-incubated with or without 1 uM BMS-536924 for 1 hour in serum free medium followed by stimulation with IGF-I (50 ng/mL) for 10 minutes. Cell monolayers are washed twice with PBS and harvested for immunoblot analysi

Cell proliferation is evaluated by [3H]thymidine incorporation after exposure to BMS-536924 for 72 hours. Cells are plated at an optimized density in 96-well plates, incubated overnight at 37 °C, and then exposed to a serial dilution of the drug. After a 72-hours incubation, cells are pulsed with 4 μCi/mL [3H]thymidine for 3 hours, trypsinized, harvested onto UniFilter-96 GF/B plates; scintillation is measured on a TopCount NXT. Results are expressed as an IC50. The mean IC50 and SD from multiple tests for each cell line are calculated. (Only for Reference)