PAWI-2: A novel inhibitor for eradication of cancer

Abstract

Cancer is a major worldwide public health problem and is still the leading cause of death in the United States. There are many types of cancer treatment but completely successful results are oftentimes not attained. It remains a challenge to develop efficacious clinically useful cancer therapies. Therapies targeting dysregulated signal transduction pathways in cancer can be efficacious anti-cancer therapies with minimal adverse effects. In this study, we focus on novel small molecule p53 Activator Wnt Inhibitor-2 (PAWI-2) that was developed by optimizing potency and pharmaceutical properties. PAWI-2 is a nontoxic DNA-damage pathway inhibitor that shows a broad spectrum of potency and significant efficacy in vitro and in vivo. This study focuses on the application of PAWI-2 to four major types of cancers including colorectal cancer (CRC), breast cancer (BC), prostate cancer (PCa), and pancreatic cancer (PC). PAWI-2 shows a novel mechanism of action (MOA) by modulating two mechanisms of cancer invasion. In cancer with unimpaired p53, PAWI-2 activates DNA-damage checkpoint and mitochondrial p53-dependent apoptotic signaling. Consistently observed in most cancer types, PAWI-2 induces phosphorylation of optineurin (OPTN) to cause G2/M cell cycle arrest. These two mechanisms operate regardless of p53 variants and/or KRAS mutation status and also manipulate the effect of PAWI-2 to overcome tumor stemness and drug resistance in PC stem cells (PCSCs). This study summarizes the development of PAWI-2 as an attractive targeted therapeutic for mechanism-driven anti-cancer drug discovery.