Abstract B22: Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo

The MYC family of transcription factors is one of the most frequently overexpressed oncogenes in human malignancies, including tumors that are derived from the nervous system. MYCN plays a causative role in neuroblastoma, a common and fatal childhood cancer of the developing sympathetic nervous system. Thus, the MYC family has been considered as a promising cancer target; however, so far, no small molecules can directly target MYC or MYCN in vivo. We have recently reported that PRMT1 functions as a key regulator of the stability and oncogenicity of MYCN. In this study, we have performed the structure-activity relationship analysis of diamidine-related PRMT1-seletive inhibitors. In correlation with their inhibition against PRMT1 in biochemical assays, these compounds showed remarkable anticancer properties both in neuroblastoma cell lines in vitro and in a preclinical mouse model of neuroblastoma in vivo. Mechanistically, these potent PRMT1 inhibitors destabilized MYCN, caused cell cycle arrest, and restored normal developmental signals of the developing sympathetic neuroblast precursors. Together, our results demonstrate that PRMT1-seletive inhibitors are promising anti-neuroblastoma agents and may represent a general strategy to target certain MYC/MYCN-driven cancers. Citation Format: Jeanne N. Hansen, Louis T. Lotta, Allison Eberhardt, Yujun George Zheng, Sen Ji, Shengyong Yang, Nina F. Schor, Xingguo Li. Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B22.