Abstract 4787: New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor

Abstract

Abstract Triple-negative breast cancer (TNBC) which constitutes 15-20% of breast cancers, is the most aggressive and chemo-resistant subtype of breast cancer and associated with the highest mortality rates of mortality among all breast cancer subtypes. TNBC is characterized by a lack of molecular targets (e.g., estrogen, progesterone, and HER2 receptors. Current treatment options for TNBC are still limited to conventional chemotherapies such as anthracyclines (e.g., doxorubicin) and taxane-based therapeutics. Identification of new molecular targets is critical for development of novel targeted treatments to improve poor patient prognosis and survival. We recently found that expression of eukaryotic elongation factor-2 kinase (EF2K), an unusual alpha kinase, is commonly upregulated in the majority of TNBC patients and associated with poor prognosis. We showed that EF2K is a potential molecular driver by promoting cell proliferation motility and invasion and drug resistance and validated it as a molecular target by RNA based therapeutic (i.e, siRNA and microRNA) in various TNBC models in mice (Tekedereli 2012, Hamurcu 2017, Bayraktar 2017). Several inhibitors of eEF2K have been described in the previous studies. However, these inhibitors have been neither specific nor potent. Small molecule inhibitor was synthesized in many steps by using different synthesis methods and also performed all of the structural analysis (FT-IR, 1H-NMR, 13C-NMR and LC-MS-MS). Computational studies were performed by using Schrödinger 2015 programme to investigate of in vitro activity of the compounds. By performing in vitro assays we identified a potent inhibitor of EF2K which inhibited p-EF2 at 1 μM (2 hours) detected by Western blots. Treatment of TNBC cells with this compound starts to inhibits cell proliferation and colony formation at 5-10 μM concentrations. The further studies are still ongoing. In conclusion, our results suggest that our newly designed small molecule may be potent EF2K inhibitor and can be used for targeting EF2K in TNBC. Note: This abstract was not presented at the meeting. Citation Format: Ferah Comert Onder, Mehmet Ay, Serdar Durdagi, Bulent Ozpolat, isik Kantarcioglu. New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4787.