title: 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells.
abstract: Ras converting enzyme 1 (Rce1) is an endoprotease that catalyzes processing of the C-terminus of Ras protein by removing -aaX from the CaaX motif. The activity of Rce1 is crucial for proper localization of Ras to the plasma membrane where it functions. Ras is responsible for transmitting signals related to cell proliferation, cell cycle progression, and apoptosis. The disregulation of these pathways due to constitutively active oncogenic Ras can ultimately lead to cancer. Ras, its effectors and regulators, and the enzymes that are involved in its maturation process are all targets for anti-cancer therapeutics. Key enzymes required for Ras maturation and localization are the farnesyltransferase (FTase), Rce1, and isoprenylcysteine carboxyl methyltransferase (ICMT). Among these proteins, the physiological role of Rce1 in regulating Ras and other CaaX proteins has not been fully explored. Small-molecule inhibitors of Rce1 could be useful as chemical biology tools to understand further the downstream impact of Rce1 on Ras function and serve as potential leads for cancer therapeutics. Structure-activity relationship (SAR) analysis of a previously reported Rce1 inhibitor, NSC1011, has been performed to generate a new library of Rce1 inhibitors. The new inhibitors caused a reduction in Rce1 in vitro activity, exhibited low cell toxicity, and induced mislocalization of EGFP-Ras from the plasma membrane in human colon carcinoma cells giving rise to a phenotype similar to that observed with siRNA knockdowns of Rce1 expression. Several of the new inhibitors were more effective at mislocalizing K-Ras compared to a potent farnesyltransferase inhibitor (FTI), which is significant because of the preponderance of K-Ras mutations in cancer.
authors.affiliation: New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates.
authors.forename: Idrees
authors.initials: I
authors.lastname: Mohammed
authors.affiliation: New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates.
authors.forename: Shahienaz E
authors.initials: SE
authors.lastname: Hampton
authors.affiliation: New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates.
authors.forename: Louise
authors.initials: L
authors.lastname: Ashall
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, United States.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Hildebrandt
authors.affiliation: Department of Chemistry, University of Georgia, Athens, GA 30602, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kutlik
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, United States.
authors.forename: Surya P
authors.initials: SP
authors.lastname: Manandhar
authors.affiliation: Department of Chemistry, University of Georgia, Athens, GA 30602, United States.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Floyd
authors.affiliation: New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Dozier
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Distefano
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, United States.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schmidt
authors.affiliation: New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates; Department of Chemistry, University of Georgia, Athens, GA 30602, United States. Electronic address: timothy.dore@nyu.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Dore
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D015125:Oxyquinoline / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D011480:Protease Inhibitors; D015125:Oxyquinoline; D010450:Endopeptidases; C491326:RCE1 protein, human; D018631:ras Proteins
keywords: Protease inhibitors; Ras converting enzyme (Rce1); Ras mislocalization