title: Developing structure-activity relationships from an HTS hit for inhibition of the Cks1-Skp2 protein-protein interaction.
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.
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Arvinder
authors.initials: A
authors.lastname: Sran
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Carroll
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Lyuben
authors.initials: L
authors.lastname: Tsvetkov
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Sheung
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Sarkiz D
authors.initials: SD
authors.lastname: Issakani
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: sshaw@rigel.com.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Shaw
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000609112:5-bromo-8-toluylsulfonamidoquinoline; D000634:Aminoquinolines; D000970:Antineoplastic Agents; C093090:CKS1B protein, human; D044786:S-Phase Kinase-Associated Proteins; D013449:Sulfonamides; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases
keywords: Anti-cancer; E3 ubiquitin ligases; Protein–protein interactions; Structure–activity relationships; p27