Polyisoprenylated methylated protein methyl esterase: a putative biomarker and therapeutic target for pancreatic cancer.
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.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Byron J
BJ
Aguilar
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Augustine T
AT
Nkembo
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Randolph
R
Duverna
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Rosemary A
RA
Poku
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Felix
F
Amissah
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Seth Y
SY
Ablordeppey
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. Electronic address: Nazarius.lamango@famu.edu.
Nazarius S
NS
Lamango
D000577:Amides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002265:Carboxylic Ester Hydrolases; C042523:protein methylesterase
PCAIs; PMPMEase; Pancreatic cancer; Polyisoprenylated cysteinyl amides; Polyisoprenylation; Prenylation