8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells

Idrees Mohammed, Shahienaz E. Hampton, Louise Ashall, Emily R. Hildebrandt, Robert A. Kutlik, Surya P. Manandhar, Brandon J. Floyd, Haley E. Smith, Jonathan K. Dozier, Mark D Distefano, Walter K. Schmidt, Timothy M. Dore

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)160-178
Number of pages19
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number2
DOIs
StatePublished - Jan 15 2016

Fingerprint

Oxyquinoline
Peptide Hydrolases
Cells
Membranes
Enzymes
Farnesyltranstransferase
Enzyme Inhibitors
Cell membranes
Neoplasms
Cell Membrane
ras Proteins
Structure-Activity Relationship
Small Interfering RNA
Cell proliferation
Libraries
Cell Cycle
Colon
Proteins
Toxicity
Cell Proliferation

Keywords

  • Protease inhibitors
  • Ras converting enzyme (Rce1)
  • Ras mislocalization

Cite this

Mohammed, I., Hampton, S. E., Ashall, L., Hildebrandt, E. R., Kutlik, R. A., Manandhar, S. P., ... Dore, T. M. (2016). 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorganic and Medicinal Chemistry, 24(2), 160-178. https://doi.org/10.1016/j.bmc.2015.11.043

8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. / Mohammed, Idrees; Hampton, Shahienaz E.; Ashall, Louise; Hildebrandt, Emily R.; Kutlik, Robert A.; Manandhar, Surya P.; Floyd, Brandon J.; Smith, Haley E.; Dozier, Jonathan K.; Distefano, Mark D; Schmidt, Walter K.; Dore, Timothy M.

In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 2, 15.01.2016, p. 160-178.

Research output: Contribution to journalArticle

Mohammed, I, Hampton, SE, Ashall, L, Hildebrandt, ER, Kutlik, RA, Manandhar, SP, Floyd, BJ, Smith, HE, Dozier, JK, Distefano, MD, Schmidt, WK & Dore, TM 2016, '8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells', Bioorganic and Medicinal Chemistry, vol. 24, no. 2, pp. 160-178. https://doi.org/10.1016/j.bmc.2015.11.043
Mohammed, Idrees ; Hampton, Shahienaz E. ; Ashall, Louise ; Hildebrandt, Emily R. ; Kutlik, Robert A. ; Manandhar, Surya P. ; Floyd, Brandon J. ; Smith, Haley E. ; Dozier, Jonathan K. ; Distefano, Mark D ; Schmidt, Walter K. ; Dore, Timothy M. / 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. In: Bioorganic and Medicinal Chemistry. 2016 ; Vol. 24, No. 2. pp. 160-178.
@article{dcc1dcf28b674a2694ae876a31f0bd4f,
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.",
keywords = "Protease inhibitors, Ras converting enzyme (Rce1), Ras mislocalization",
author = "Idrees Mohammed and Hampton, {Shahienaz E.} and Louise Ashall and Hildebrandt, {Emily R.} and Kutlik, {Robert A.} and Manandhar, {Surya P.} and Floyd, {Brandon J.} and Smith, {Haley E.} and Dozier, {Jonathan K.} and Distefano, {Mark D} and Schmidt, {Walter K.} and Dore, {Timothy M.}",
year = "2016",
month = "1",
day = "15",
doi = "10.1016/j.bmc.2015.11.043",
language = "English (US)",
volume = "24",
pages = "160--178",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "2",

}

TY - JOUR

T1 - 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells

AU - Mohammed, Idrees

AU - Hampton, Shahienaz E.

AU - Ashall, Louise

AU - Hildebrandt, Emily R.

AU - Kutlik, Robert A.

AU - Manandhar, Surya P.

AU - Floyd, Brandon J.

AU - Smith, Haley E.

AU - Dozier, Jonathan K.

AU - Distefano, Mark D

AU - Schmidt, Walter K.

AU - Dore, Timothy M.

PY - 2016/1/15

Y1 - 2016/1/15

N2 - 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.

AB - 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.

KW - Protease inhibitors

KW - Ras converting enzyme (Rce1)

KW - Ras mislocalization

UR - http://www.scopus.com/inward/record.url?scp=84951802550&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951802550&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2015.11.043

DO - 10.1016/j.bmc.2015.11.043

M3 - Article

VL - 24

SP - 160

EP - 178

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 2

ER -