Subclasses of patients who do not express current cancer drug targets and are resistant to modern therapies are being uncovered. Identification of cancer biomarkers and novel targets is important for developing more effective therapies. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are being designed to target polyisoprenylated methylated protein methyl esterase (PMPMEase), a key enzyme of the polyisoprenylation pathway. Effective inhibition of this enzyme results in cancer cell death possibly through interference with polyisoprenylated protein metabolism and function. Such inhibitors may serve as lead compounds for the development of drugs to address an area of unmet need. This includes cancer patients with mutated hyperactive Ras whose tumors are resistant to MAbs and kinase inhibitors targeting EGFR. Rational drug design, in silico analysis, and enzymatic assay have identified high affinity, specific PMPMEase inhibitors with micromolar Ki values. Herein, we present the design and synthesis of novel PCAIs and their chemical and pharmacological properties.

Polyisoprenylated cysteinyl amide inhibitors of polyisoprenylated methylated protein methyl esterase

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.