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PAWI-2: A novel inhibitor for eradication of cancer

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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.

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Acknowledgements

We acknowledge all the coworkers and collaborators cited in the references that contributed to this work. We are grateful to the financial support of the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM).

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  1. Human BioMolecular Research Institute, San Diego, CA, 92121, USA

    Jiongjia Cheng & John R. Cashman

  2. ChemRegen, Inc., San Diego, CA, 92121, USA

    Jiongjia Cheng & John R. Cashman

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  1. Jiongjia Cheng
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  2. John R. Cashman
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Dedication: This study is dedicated to Professor Robert Hanzlik on the occasion of his retirement from the University of Kansas. As a graduate student working under Professor Hanzlik and later as a practicing scientist, I learned a great deal from Bob. He provided very thoughtful perspectives on science, teamwork, and professional networking. Most importantly, he taught me about the joy of science. He was kind, good-hearted, and firm—all virtues of a compassionate teacher and wonderful mentor. Because I worked on a sulfur-containing compound under his direction, it is only fitting that the story told herein is about a new approach to addressing cancer with sulfur-containing compound PAWI-2.

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Cheng, J., Cashman, J.R. PAWI-2: A novel inhibitor for eradication of cancer. Med Chem Res 29, 1147–1159 (2020). https://doi.org/10.1007/s00044-020-02575-8

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