Aguilar Byron J, Nkembo Augustine T, Duverna Randolph, Poku Rosemary A, Amissah Felix, Ablordeppey Seth Y, Lamango Nazarius S
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Eur J Med Chem. 2014 Jun 23;81:323-33. doi: 10.1016/j.ejmech.2014.05.018. Epub 2014 May 9.
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.
胰腺癌是最致命的肿瘤，5年生存率低于6%。超过90%的病例存在K-Ras突变，由于缺乏有效治疗方法，这些病例最难治疗。在此，我们发现聚异戊二烯化甲基化蛋白甲酯酶（PMPMEase）在93%的胰腺导管腺癌中过表达。我们还展示了聚异戊二烯化半胱氨酰胺抑制剂（PCAIs），这些新型化合物设计有特定结构元件，以实现最佳体内活性并选择性破坏聚异戊二烯化介导的蛋白质功能。PCAIs抑制PMPMEase的Ki值范围为3.7至20 μM。胰腺癌Mia PaCa-2和BxPC-3细胞系的48小时EC50值低至1.9 μM，而在20 μM时，法尼基硫代水杨酸和法尼基硫代酰胺无效。因此，PCAIs有可能作为治疗胰腺癌和其他由Ras及相关G蛋白介导的生长信号通路过度活跃的癌症的有效疗法。
