Preclinical characterization of BAY 73-4506: A kinase inhibitor with broad spectrum antitumor activity targeting oncogenic and angiogenic kinases

B260 Background: Tumor growth and progression are dependent of oncogenic signaling networks formed by cellular kinases. Receptor tyrosine kinases (RTK) such as, KIT, RET, PDGFR, and VEGFR are activated in several solid tumors and contribute to tumor progression. Several agents targeting oncogenic RTK have shown anti-tumor activity in the clinic.
 Results: BAY 73-4506 is a novel potent inhibitor of the angiogenic RTK (VEGFR-1, -2 and -3 and PDGFR-β), the oncogenic RTK (KIT, RET), and serine/threonine kinases (p38MAPK and RAF). In cellular assays, BAY 73-4506 showed potent activity against VEGFR-2 (IC50=4 nM), VEGFR-3 (IC50=150 nM), and PDGFR-β (IC50=90 nM). Vascular cell proliferation was strongly inhibited in human umbilical vein endothelial cells (IC50=4 nM) and human aortic smooth muscle cells (IC50=120 nM). BAY 73-4506 inhibited tumor cell proliferation in a subset of human tumor cell lines of different histological types. Furthermore, BAY 73-4506 inhibited activated mutant KIT (KITK642E, IC50=20 nM) and RET (RETC643W, IC50=25 nM) and imatinib-resistant variants of KIT Δ557-558 with a secondary mutation (IC50 range, 12 to 129 nM). BAY 73-4506 inhibited p38MAPK signaling (IC50 = 120 nM) in anisomycin-stimulated DLD-1 cells (phosphorylation of ATF-1 and MSK1/2). BAY 73-4506 demonstrated broad spectrum anti-tumor activity in murine xenograft models, with complete tumor stasis observed in most models when dosed orally at 10 mg/kg QD. Partial tumor responses were observed in Colo-205 (colon), 786-O (kidney), and MDA-MB-231 (breast) models at 30 or 100 mg/kg. Immunohistochemistry analysis of BAY 73-4506-treated tumors with an anti-CD31 (endothelial cell marker) antibody showed significant reduction in microvessel area or neovascularization. Consistent with the effects reported for VEGFR signaling inhibitors, using a recombinant VEGF in a rat model, BAY 73-4506 dose-dependently reduced VEGF-mediated decrease in blood pressure (~80% reduction of hypotensive response by 1 mg/kg i.v. BAY 73-4506). Similar results were observed with M2 metabolite of BAY 73-4506.
 Conclusions: BAY 73-4506 is a novel kinase inhibitor with potent activity against oncogenic and angiogenic receptor tyrosine and ser/thr kinases. BAY 73-4506 possesses a broad spectrum anti-tumor activity in preclinical cancer models and is currently undergoing phase I clinical trials.