Optimizing the aryl-triazole of cjoc42 for enhanced gankyrin binding and anti-cancer activity

  • Bioorg Med Chem Lett. 2020 Sep 1;30(17):127372. doi: 10.1016/j.bmcl.2020.127372.
Dipti Kanabar  1 ,  Pamela Farrales  1 ,  Abbas Kabir  1 ,  Daniel Juang  1 ,  Manu Gnanmony  2 ,  Joseph Almasri  3 ,  Nicolas Torrents  1 ,  Snehal Shukla  1 ,  Vivek Gupta  1 ,  Vikas V Dukhande  1 ,  Amber D'Souza  2 ,  Aaron Muth  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
  • 2. Department of Pediatrics, Hematology and Oncology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
  • 3. Department of Chemistry, College of Liberal Arts and Sciences, St. John's University, Queens, NY 11439, USA.
PMID: 32738965 DOI: 10.1016/j.bmcl.2020.127372
Abstract

Gankyrin is an oncoprotein overexpressed in numerous Cancer types and appears to play a key role in regulating cell proliferation, cell growth, and cell migration. These roles are largely due to gankyrin's protein-protein interaction with the 26S Proteasome. We previously published a study exploring the aryl sulfonate ester of cjoc42 in an effort to enhance gankyrin binding and inhibit Cancer cell proliferation. In order to further improve the gankyrin binding ability of the cjoc42 scaffold, an extensive SAR for the aryl-triazole moiety of cjoc42 was developed. Our cjoc42 derivatives exhibited enhanced gankyrin binding, as well as enhanced antiproliferative activity against Hep3B, HepG2, A549, and MDA-MB-231 Cancer cell lines.

Keywords
Antiproliferation; Breast cancer; Gankyrin; Liver cancer; Lung cancer; Protein-protein interactions.