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.

中文翻译：

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PAWI-2：一种用于根除癌症的新型抑制剂

癌症是全球主要的公共卫生问题，仍然是美国死亡的主要原因。有许多类型的癌症治疗方法，但有时无法获得完全成功的结果。开发有效的临床有用的癌症疗法仍然是一个挑战。针对癌症中信号转导途径失调的疗法可以是有效的抗癌疗法，且副作用最小。在这项研究中，我们重点研究新型的小分子p 53 A激动剂W nt Inhibitor- 2（PAWI-2）是通过优化效能和药物特性而开发的。PAWI-2是一种无毒的DNA损伤途径抑制剂，在体外和体内均显示出广谱的效能和显着的功效。这项研究的重点是PAWI-2在四种主要类型的癌症中的应用，包括结直肠癌（CRC），乳腺癌（BC），前列腺癌（PCa）和胰腺癌（PC）。PAWI-2通过调节两种癌症入侵机制显示了一种新的作用机制（MOA）。在具有未受损的p53的癌症中，PAWI-2激活DNA损伤检查点和线粒体p53依赖性凋亡信号。在大多数癌症类型中一致观察到，PAWI-2诱导optineurin（OPTN）的磷酸化导致G2 / M细胞周期停滞。不管p53变体和/或KRAS突变状态如何，这两种机制都起作用，并且还操纵PAWI-2的作用来克服PC干细胞（PCSC）中的肿瘤干性和耐药性。这项研究总结了PAWI-2作为一种机制驱动的抗癌药物发现的有吸引力的靶向治疗剂的发展。