BMS-354825 potently inhibits multiple selected oncogenic tyrosine kinases and possesses broad-spectrum antitumor activities in vitro and in vivo

Proc Amer Assoc Cancer Res, Volume 46, 2005 675 BMS-354825 is a novel 2-substituted aminopyrimidinyl-thiazole-5-carboxamide analog currently being developed by Bristol-Myers Squibb for the treatment of solid tumors and Imatinib-resistant and -sensitive leukemias (Shah et al, Science , 305, 399-401, 2004). BMS-354825 competes with ATP for the ATP-binding site in the kinase domain of selected and related oncogenic receptor and non-receptor protein tyrosine kinases (PTKs), including BCR-ABL, SRC family kinases, c-KIT, EPH and PDGF receptors. These PTKs have been strongly linked to multiple forms of human cancers and their dysregulations are critical to the pathophysiology of malignancies: uncontrolled proliferation, inappropriate adhesion, heightened motility and metastatic potential, resistance to apoptosis, and angiogenesis promotion. In in vitro kinase assays, BMS-354825 potently inhibits these PTKs at subnanomolar to low nanomolar concentrations: with IC50 as follows: SRC family kinases (SRC = 0.55 nM, LCK = 1.1 nM, YES = 0.41 nM, FYN = 0.2 nM); BCR-ABL (<3 nM); c-KIT (13 nM); EPHA2 (17 nM) and PDGFβ receptor (28 nM). In cellular assays, BMS-354825 at clinically achievable concentrations (< 1.0 μM) inhibited the proliferation of 11 of 23 lung (48%), 9 of 31 colon (29%) and 7 of 23 breast (30%) cancer cell lines tested todate using the MTS assay. In preclinical chemotherapy trials against a random panel of thirteen solid tumors grown in mice, BMS-354825 significantly inhibited the growth of 6 of 13 xenografts (46%) at doses producing drug exposure similar to those currently achieved in ongoing phase I clinical trials. Responsive tumor types include breast, prostate, colon, pancreatic, sarcoma and small cell lung cancers. These results suggest that BMS-354825 may have therapeutic utilities in a broad-spectrum of cancer types. BMS-354825 is currently in clinical trials in both BCR-ABL dependent leukemias and in solid malignancies.