2. Academic Validation
  3. Structural modification of the aryl sulfonate ester of cjoc42 for enhanced gankyrin binding and anti-cancer activity

Structural modification of the aryl sulfonate ester of cjoc42 for enhanced gankyrin binding and anti-cancer activity

  • Bioorg Med Chem Lett. 2020 Feb 15;30(4):126889. doi: 10.1016/j.bmcl.2019.126889.
Dipti Kanabar 1,  Pamela Farrales 1,  Manu Gnanamony 2,  Joseph Almasri 3,  Ehab M Abo-Ali 1,  Younos Otmankel 1,  Henna Shah 1,  Dawn Nguyen 1,  Mark El Menyewi 1,  Vikas V Dukhande 1,  Amber D'Souza 2,  Aaron Muth 4
Affiliations

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 Peoria, Peoria, IL 61605, USA.
  • 3 Department of Chemistry, College of Liberal Arts and Sciences, St. John's University, Queens, NY 11439, USA.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: mutha@stjohns.edu.
PMID: 31902711 DOI: 10.1016/j.bmcl.2019.126889
Abstract

Gankyrin is an oncogenic protein involved in various biological processes, such as cellular growth and proliferation. Its overexpression in certain cancers results in an increase of gankyrin-mediated protein-protein interactions (PPIs), leading to Cancer proliferation. To date, only one small molecule (cjoc42) has been identified to bind gankyrin, which simultaneously inhibits its interaction with the 26S Proteasome. Despite this advance, 2nd generation inhibitors are needed to improve gankyrin binding and cellular efficacy. To this end, an extensive SAR for the aryl sulfonate ester moiety of the cjoc42 scaffold was explored, and showed that substitutions at the 2-, 3-, and 4-positions manifested significant increases in gankyrin binding, resulting in the most potent Binders of gankyrin to date. Subsequent cell-based assay evaluation of our derivatives demonstrated antiproliferative activity against pediatric liver Cancer cell lines Hep3B and HepG2, which was not previously observed for cjoc42.

Keywords

Antiproliferation; Gankyrin; Liver cancer; Protein–protein interactions.

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