BMS-599626 hydrochloride

BMS-599626 (AC-480) is a potent, selective inhibitor of EGFR and HER2 with IC50 of 20 nM and 30 nM; displays 8-fold less potency to HER4, >100-fold to VEGFR2, c-Kit, Lck, MET etc; inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2; shows potent antitumor activity in a human breast tumor KPL-4 xenograft; orally efficacious.Breast Cancer Phase 1 Discontinued (In Vitro) :BMS-599626 Hydrochloride inhibits the proliferation of tumor cells that are dependent on HER1/HER2 signaling.BMS-599626 Hydrochloride (0.03-8 μM; 1 huors) results in the inhibition of receptor autophosphorylation, as well as MAPK phosphorylation, with IC50s of 0.3 and 0.22 μM, respectively, in Sal2 cells which express a CD8HER2 fusion protein.BMS-599626 Hydrochloride abrogates HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50s in the range of 0.24 to 1 μM.In GEO cells, HER1 phosphorylation is stimulated by treatment with EGF and is inhibited by BMS-599626 Hydrochloride (IC50=0. 75 μM) .There is also nearly complete inhibition of EGF-dependent MAPK (0. 8 μM) but only partial inhibition of AKT signaling.The latter likely reflects the activation of AKT by multiple upstream signals.Treatment of N87 cells with BMS-599626 Hydrochloride leads to the inhibition of HER2 (0. 38 μM), which is expressed to a high level because of gene amplification, as well as MAPK and AKT phosphorylation (0.35 μM for both) .At the molecular level, in HN-5 cells the agent (BMS-599626 Hydrochloride) inhibits the expression of pEGFR, pHER2, cyclins D and E, pRb, pAkt, pMAPK, pCDK1 and 2, CDK 6, and Ku70 proteins. BMS-599626 Hydrochloride also induced accumulation of cells in the G1 cell cycle phase, inhibited cell growth, enhanced radiosensitivity, and prolonged the presence of γ-H AX foci up to 24 h after radiation. (In Vivo) :BMS-599626 Hydrochloride (60-240 mg/kg; p.o.; daily for 14 days) results in a dose-dependent inhibition of Sal2 tumor growth.BMS-599626 Hydrochloride treatment results in the inhibition of GEO xenograft tumor growth when given once daily for 14 days. In addition to efficacy in the Sal2, GEO, and KPL4 models, BMS-599626 has similar antitumor activity in other HER2 amplified xenograft models including the BT474 breast and N87 gastric tumors, as well as other HER1-overexpressing non-small-cell lung tumors (A549 and L2987) .BMS-599626 Hydrochloride given before and during irradiation improved the radioresponse of HN5 tumors in vivo.