Developing structure-activity relationships from an HTS hit for inhibition of the Cks1-Skp2 protein-protein interaction.

Structure-activity relationships have been developed around 5-bromo-8-toluylsulfonamidoquinoline 1 a hit compound in an assay for the interaction of the E3 ligase Skp2 with Cks1, part of the SCF ligase complex. Disruption of this protein-protein interaction results in higher levels of CDK inhibitor p27, which can act as a tumor suppressor. The results of the SAR developed highlight the relationship between the sulfonamide and quinoline nitrogen, while also suggesting that an aryl substituent at the 5-position of the quinoline ring contributes to the potency in the interaction assay. Compounds showing potency in the interaction assay result in greater levels of p27 and have been shown to inhibit cell growth of two p27 sensitive tumor cell lines.
AuthorsRajinder Singh, Arvinder Sran, David C Carroll, Jianing Huang, Lyuben Tsvetkov, Xiulan Zhou, Julie Sheung, John McLaughlin, Sarkiz D Issakani, Donald G Payan, Simon J Shaw
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 22 Pg. 5199-202 (Nov 15 2015) ISSN: 1464-3405 [Electronic] England
PMID26463131 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.

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