Polyisoprenylated Cysteinyl Amide Inhibitors: A Novel Approach to Controlling Cancers with Hyperactive Growth Signaling.

Polyisoprenylated Cysteinyl Amide Inhibitors: A Novel Approach to Controlling Cancers with Hyperactive Growth Signaling. Curr Med Chem. 2020 Nov 11;: Authors: Lamango NS, Nkembo AT, Ntantie E, Tawfeeq N Abstract Aberrant activation of monomeric G-protein signaling pathways drives some of the most aggressive cancers. Suppressing these hyperactivities has been the focus of efforts to obtain targeted therapies. Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in various cancers. Its inhibition induces the death of cancer cells that harbor the constitutively active K-Ras proteins. Furthermore, the viability of cancer cells driven by factors upstream of KRas, such as overexpressed growth factors and their receptors or the mutationally-activated receptors is also susceptible to PMPMEase inhibition. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were thus designed to target cancers with hyperactive signaling pathways involving the G-proteins. The PCAIs were however poor inhibitors of PMPMEase, with Ki values ranging from 3.7 to 20 µM. On the other hand, they inhibited cell viability, proliferation, colony formation, induced apoptosis in cells with mutant K-Ras and inhibited cell migration and invasion with EC50 values of 1 to 3 M. HUVEC tube formation was inhibited at submicromolar concentrations through their disruption of actin filament organization. At the molecular level, the PCAIs at 2 to 5 ...
Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research