Abstract 1483: Development of FUBP1 inhibitors to reprogram pancreatic cancer cells into an anti-cancer phenotype

Abstract

Abstract The purpose of this project was to identify small molecules which reprogram tumor cells into an anticancer phenotype. Far upstream binding protein 1 (FUBP1) has been identified as a master regulator of a panel of genes involved in tumor survival including c-Myc and p21. FUBP1 controls gene expression by binding to specific far upstream element (FUSE) DNA sequences of the promoters of key tumor survival genes to regulate their transcription to provide a pro-tumor phenotype (high c-Myc, low p21). This makes FUBP1 a novel therapeutic target as its inhibition reprograms tumors to an anti-cancer phenotype (low c-Myc, high p21). This report describes the development of novel anthranilic acid derivatives which bind to FUBP1 (as shown by ChIP and gel shift assays) and modulate the mRNA and protein expression (qRT-PCR and Western) of FUSE-controlled genes (e.g., c-Myc and p21). The lead compound UCF699 was shown to reprogram pancreatic ductal adenocarcinoma (PDAC) cells into an anti-cancer phenotype in a dose-dependent manner and inhibit pancreatic cancer cell growth. In summary, the ability of UCF699 to control the expression of multiple FUSE-controlled genes and to reprogram tumor cells into an anti-cancer phenotype provides an exciting new way to treat pancreatic tumors. Citation Format: Alexandra Bunea, Christopher Polera, Aiste Dobrovolskaite, Holly Moots, Otto Phanstiel. Development of FUBP1 inhibitors to reprogram pancreatic cancer cells into an anti-cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1483.