ENMD-2076

ENMD-2076 is a multi-kinase inhibitor that inhibits FMS-related tyrosine kinase 3 (FLT3), RET, and Aurora A kinase with IC₅₀ values of 1.86, 10.4, and 14 nM, respectively.¹ It inhibits additional kinases involved in angiogenesis such as VEGFR3, PDGFRα, and FGFR2, among others, with IC₅₀ values of less than 100 nM. It inhibits proliferation of several human triple-negative breast cancer (TNBC) cell lines with IC₅₀ values of less than 1 µM, halts the cell cycle at the G₂ phase, and induces apoptosis.² Oral administration of ENMD-2076 (200 mg/kg), reduces proliferation, enhances p53- and p73-mediated cancer cell apoptosis and senescence, and inhibits growth of sensitive primary tumors in a TNBC mouse xenograft model.³ It also decreases tumor vascular permeability and perfusion and inhibits tumor growth in human TNBC and colorectal cancer mouse xenograft models when administered orally at a dose of 100 mg/kg.^2,4

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1. Fletcher, G.C., Brokx, R.D., Denny, T.A., et al. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol. Cancer Ther. 10(1), 126-137 (2011).

2. Diamond, J.R., Eckhardt, S.G., Tan, A.C., et al. Predictive biomarkers of sensitivity to the aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical breast cancer models. Clin. Cancer Res. 19(1), 291-303 (2013).

3. Ionkina, A.A., Tentler, J.J., Kim, J., et al. Efficacy and molecular mechanisms of differentiated response to the aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical models of p53-mutated triple-negative breast cancer. Front. Oncol. 7(94), (2017).

4. Tentler, J.J., Bradshaw-Pierce, E.L., Serkova, N.J., et al. Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models. Clin. Cancer Res. 16(11), 2989-2998 (2010).