| BMS-536924 is a novel small-molecule inhibitor which prevents activity of the insulin-like growth factor receptor kinase. BMS-536924 has equal potency against the insulin receptor. BMS-536924 inhibits insulin-like growth factor receptor (IGF-1R) with an IC50 of 100 nM while BMS-536924 prevents cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP3A4-BFC and CYP3A4-BzRes with IC50s of 34, 1.2, 2, 0.5 and 5.3 μM, respectively. BMS-536924 inhibits insulin receptor (IR), FAK and LcK with IC50s of 73, 150 andd 341 nM, respectively. BMS-536924 effectively inhibits proliferation of IGR-1R Sal cell line in vitro. BMS-536924 disrupts Akt and MAPK phosphorylation. BMS-536924 blocks cellular proliferation in prostate, breast, and colon tumor cell lines. BMS-536924 prevents RD1 (rhabdomyosarcoma), MDA PCa-2b cells, Colo 205 cells, Geo cells and MCF-7 cells with IC50 of 202, 194, 212, 320 and 460 nM, respectively. [1] A significant prevention of 4T1 cell proliferation produces with increasing doses of BMS-536924 in the presence of insulin or IGF1.[2] BMS-536924 is sensitive against several cell lines including TC32, LG, VW, TC71, RDES, Rh1, JD cell lines with IC50 of 55, 63, 101, 119, 123, 135 and 232 nM, respectively. [3] BMS-536924 inhibits OV202 cell lines with an IC50 of 5 μM. [4] BMS-536924 is effective against the nonengineered Colo205 human colon carcinoma model. Oral injection of BMS-536924 on a once a day schedule (100−300 mg/kg) or a twice a day schedule (50, 100 mg/kg) demonstrates antitumor activity in nonengineered Colo205 human colon carcinoma tumor model. In pharmacokinetics, Cmax,po of BMS-536924 in mouse and rat is 3.8 and 69 μM, respectively. Less than 5% of BMS-536924 is eliminated in bile and urine, with the major metabolites being associated with oxidation and cleavage of the morpholine ring. BMS-536924 is highly protein bound (>99% in mouse and human plasma). [1] BMS-536924 inhibits 4T1 tumor growth in vivo. Reduction in tumor growth relative to control is by 50% (BMS-536924: 409 mm3, control: 852 mm3). [2] |
