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

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

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5199-202. doi: 10.1016/j.bmcl.2015.09.067.
Rajinder Singh 1,  Arvinder Sran 1,  David C Carroll 1,  Jianing Huang 1,  Lyuben Tsvetkov 1,  Xiulan Zhou 1,  Julie Sheung 1,  John McLaughlin 1,  Sarkiz D Issakani 1,  Donald G Payan 1,  Simon J Shaw 2
Affiliations

Affiliations

  • 1 Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
  • 2 Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: sshaw@rigel.com.
PMID: 26463131 DOI: 10.1016/j.bmcl.2015.09.067
Abstract

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.

Keywords

Anti-cancer; E3 ubiquitin ligases; Protein–protein interactions; Structure–activity relationships; p27.

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