Novel Metformin Analogues for Treatment of Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDCA) is a leading cause of cancer death in the US. Patients diagnosed with PDCA generally present advanced disease poor prognosis and limited treatment options. African American patients have higher incidence mortality than Caucasian or any other ethnic group. Different factors been attributed to contribute this health disparity, among them Diabetes Mellitus type 2. To address need for new therapeutic approaches, we note epidemiologic reports that diabetes mellitus-type 2 treated biguanide drug metformin, but not antidiabetic drugs, reduced risk an increased survival rate those PDCA. The main physiologic effect metformin lower blood glucose reduce hyperinsulinemia associated insulin resistance. In cell, stimulates AMP-activated protein kinase (AMPK) turn inhibits mTORC1 which integrates signals from array intracellular pathways regulate cell growth. Recent clinical trials describe modest antiproliferative effects use neoadjuvant no significant benefit occurred when was dosed at glycemic control levels cancers. These findings suggest development more potent anticancer analogues may help boost patient survival. Hence, designed screening these compounds preclinical models show selected are efficacious blocking tumor progression parental doses. Using proliferation assays vitro, cells (Panc 1, MIA Paca-2) were 72-hrs analogues, greater dose-dependent inhibition found as compared (P<0.001). Further, apoptosis also markedly induced by (P<0.01). Antitumor part activation LKB1-AMPK downstream blockade mTOR signaling, often cells. vitro 24-hrs, find induce AMPK phosphorylation suppression thus synthesis proliferation. With vivo PANC 1 xenograft model nude mice, lead given oral gavage daily significantly inhibited over 28-days appropriate controls (P<0.0001). Our activity promise targeted therapeutics afflicted deadly disease. [Funded NIH/NCI R21CA176337 U54 CA143930]