LAUSR

Background: Dihydroorotate dehydrogenase (DHODH) is an enzyme which is critically involved in process of de novo pyrimidine biosynthesis. Therefore, it plays important roles in cell proliferation, mitosis and cellular metabolism. Importantly, overexpression of DHODH has been found in various types of malignant tumors including melanoma, myeloma, and lymphoma. Moreover, from Oncomine database, we observed that colorectal and kidney cancers and lymphoma have much higher expression of DHODH compared to normal cells. These findings suggest that DHODH could be a promising target for cancer therapy. Recently, we have designed and synthesized a novel small molecule inhibitor (RP7214) of DHODH and found that it has potent inhibitory effects in acute myeloid leukemia. However, the inhibitory effect of RP7214 on solid tumor-derived cell lines and the downstream oncogenic markers is not completely understood. Methods:In vitro studies aimed at elucidating the effects of RP7214 on cell proliferation and the underlying molecular mechanisms were conducted using breast adenocarcinoma (MDA-MB-231) and colorectal carcinoma cell lines (HT-29 and HCT-116). We also investigated whether RP7214 could potentiate the anti-cancer activities of proven chemotherapeutics such as Verzenio, Doxorubicin, and Oxaliplatin, for the treatment of breast and colorectal cancers. Results: RP7214 significantly (P Conclusions: Based on these results, we conclude that RP7214 could be a promising DHODH inhibitor used in combination with conventional chemotherapeutics for better treatment of breast and colorectal cancers. We are now conducting animal experiment to confirm the value of RP7214 in vivo in combination treatment of breast and colorectal cancers. Citation Format: Asfar S. Azmi, Amro Aboukameel, Mohammad Najeeb Al-Hallak, Philip A. Philip, Kumar Penmetsa, Srikant Visvanadha, Gabriel Mpilla, Rachel Sexton, Ramzi M. Mohammad. A novel, small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), RP7214, potentiates activity of chemotherapeutics in breast and colorectal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 234.