TY - JOUR
T1 - Polyisoprenylated methylated protein methyl esterase
T2 - A putative biomarker and therapeutic target for pancreatic cancer
AU - Aguilar, Byron J.
AU - Nkembo, Augustine T.
AU - Duverna, Randolph
AU - Poku, Rosemary A.
AU - Amissah, Felix
AU - Ablordeppey, Seth Y.
AU - Lamango, Nazarius S.
N1 - Funding Information:
The research reported in this publication was supported by the National Institute On Minority Health and Health Disparities (NIMHD) of the National Institutes of Health (NIH) under Award Number G12 MD007582 (previous award NIH/NCRR/RCMI G12 RR03020). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2014/6/23
Y1 - 2014/6/23
N2 - 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.
AB - 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.
KW - PCAIs
KW - PMPMEase
KW - Pancreatic cancer
KW - Polyisoprenylated cysteinyl amides
KW - Polyisoprenylation
KW - Prenylation
UR - http://www.scopus.com/inward/record.url?scp=84901356882&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.05.018
DO - 10.1016/j.ejmech.2014.05.018
M3 - Article
C2 - 24852279
AN - SCOPUS:84901356882
SN - 0223-5234
VL - 81
SP - 323
EP - 333
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -