Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

Byron J. Aguilar, Augustine T. Nkembo, Randolph Duverna, Rosemary A. Poku, Felix Amissah, Seth Y. Ablordeppey, Nazarius S. Lamango

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Pancreatic cancer is the most deadly neoplasm with a 5-year survival rate of less than 6%. Over 90% of cases harbor K-Ras mutations, which are the most challenging to treat due to lack of effective therapies. Here, we reveal that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in 93% of pancreatic ductal adenocarcinoma. We further present polyisoprenylated cysteinyl amide inhibitors (PCAIs) as novel compounds designed with structural elements for optimal in vivo activities and selective disruption of polyisoprenylation-mediated protein functions. The PCAIs inhibited PMPMEase with Ki values ranging from 3.7 to 20 μM. The 48 h EC50 values for pancreatic cancer Mia PaCa-2 and BxPC-3 cell lines were as low as 1.9 μM while salirasib and farnesylthiosalicylamide were ineffective at 20 μM. The PCAIs thus have the potential to serve as effective therapies for pancreatic and other cancers with hyperactive growth signaling pathways mediated by Ras and related G-proteins.

Original languageEnglish
Pages (from-to)323-333
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume81
DOIs
StatePublished - Jun 23 2014

Keywords

  • PCAIs
  • PMPMEase
  • Pancreatic cancer
  • Polyisoprenylated cysteinyl amides
  • Polyisoprenylation
  • Prenylation

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