Abstract 2433: A novel MDM2 inhibitor suppresses breast cancer growth and metastasis

Abstract

Abstract The MDM2 oncogene is amplified and/or overexpressed in many human cancers, including breast cancer, and it has been suggested as a molecular target for treating human cancers. MDM2 is a major negative regulator of tumor suppressor p53. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. Therefore, new strategies to target MDM2 are desirable. The present study was designed to develop a new class of MDM2 inhibitors that exert anti-breast cancer activity, regardless of p53 status in the cancers. The selective MDM2 inhibitors were discovered by a computational structure-based screening, yielding a lead compound, termed JapA. Fluorescence polarization (FP)-based binding assay and cellular thermal shift assay were performed to determine the binding between MDM2 and JapA. Its cytotoxicity was initially evaluated in breast cancer cell lines (MCF-7, MCF-7/p53−/−, MDA-MB-231, and MDA-MB-468) and normal human breast cells (MCF-10A). Its anti-breast cancer activities were further assessed in in vitro and in vivo MCF-7 and MDA-MB-231 models. The molecular mechanisms for its targeting effects on MDM2 were elucidated in various cell models in vitro and in vivo. We further found that JapA selectively inhibited breast cancer cell growth, decreased cell proliferation, and induced G2/M phase arrest and apoptosis in breast cancer cells through an MDM2-dependent mechanism, regardless of p53 status. In MCF-7 and MDA-MB-231 xenograft models, JapA inhibited MDM2 and suppressed tumor growth and lung metastasis in a dose-dependent manner, without host toxicity. Furthermore, JapA directly bound to MDM2 protein and reduced MDM2 levels in cancer cells in vitro and in vivo by promoting MDM2 protein degradation and inhibiting MDM2 transcription, which is distinct from the existing MDM2 inhibitors. In conclusion, JapA represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and might be developed as a novel cancer therapeutic agent. (Supported by the NIH R01 CA112029, R01 CA121211, and R01 CA186662) Citation Format: Jiang-Jiang Qin, Wei Wang, Sukesh Voruganti, Ruiwen Zhang. A novel MDM2 inhibitor suppresses breast cancer growth and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2433. doi:10.1158/1538-7445.AM2015-2433