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

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 4; pp. 126889 - 126893
• Main Authors: Kanabar, Dipti, Farrales, Pamela, Gnanamony, Manu, Almasri, Joseph, Abo-Ali, Ehab M., Otmankel, Younos, Shah, Henna, Nguyen, Dawn, El Menyewi, Mark, Dukhande, Vikas V., D'Souza, Amber, Muth, Aaron
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2020; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferation; Benzenesulfonates - chemical synthesis; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Binding Sites; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Esters - chemistry; Gankyrin; Humans; Life Sciences & Biomedicine; Liver cancer; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein Structure, Tertiary; Protein–protein interactions; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Science & Technology; Sulfonic Acids - chemistry; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Antiproliferation; Liver cancer; Protein–protein interactions; Gankyrin; PROTEIN; P28(GANK); ONCOPROTEIN GANKYRIN; Protein-protein interactions; DISCOVERY; RB; C/EBP-ALPHA; S6 ATPASE; DEGRADATION; EXPRESSION; TUMORIGENESIS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.126889

[Display omitted] 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.