Abstract 1804: Identification of novel NM23 inhibitors as potential anti-angiogenic agents

Abstract

Abstract Exogenous nucleoside diphosphate kinase (eNDPK or NM23) has been shown to promote endothelial cell proliferation and migration and tumor-mediated angiogenesis. This is facilitated by its transphosphorylase activity, in which a gamma terminal phosphate group from a triphosphate nucleoside is transferred to a diphosphate nucleoside, resulting in elevated ATP levels. Increased levels of ATP in the tumor microenvironment can activate purinergic receptors (P2Y1) on adjacent endothelial cells to promote angiogenesis, independent of VEGF stimulation. Triple negative human breast cancer (MDA-MB-231) cells have been shown to elaborate exosomes that contain NM23. These exosomes have implications in targeting specific tissues/cells to promote angiogenesis and tumorigenesis. Our lab has shown that inhibition of eNDPK and the P2Y1 receptor reduces endothelial cell tubulogenesis (Rumjahn, et al., 2007) and breast cancer metastasis (Yokdang, et al., 2015). Therefore, targeted inhibition of eNDPK may have implications as a treatment for early tumor-mediated angiogenesis. For this study, we utilized a transphosphorylation activity assay to perform a drug screen on compounds from the Prestwick chemical library. Recombinant NDPK-B was added to FDA-approved drug compounds along with ADP and UTP substrates. Subsequent ATP generation was detected with a luciferase luciferin reaction. Decreased luminescence signal/inhibition of NDPK was compared to ellagic acid control, a known inhibitor of NDPK. From our initial screen, we identified eight potential compounds that inhibited NDPK at comparable levels to ellagic acid. These eight compounds were further examined to determine the dose response curve. We found that Chicago Sky Blue 6B inhibited NDPK at an IC50 value of 1.88µM. The results from this study demonstrate a drug screening method to discover alternative small molecule inhibitors of NDPK as a potential treatment of angiogenesis and breast cancer metastasis. Citation Format: Senny Nordmeier, Jon Evasovic, Suzann Duan, Ryan Wuebbles, Dean J. Burkin, Iain L. Buxton. Identification of novel NM23 inhibitors as potential anti-angiogenic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1804. doi:10.1158/1538-7445.AM2017-1804