• Novel Extracellular Signal-Regulated Kinase (ERK) Targeted Inhibitors Effects on Apoptotic Signaling: A Potential Cancer Therapy

      Boston, Sarice Renee; Shapiro, Paul, Ph.D. (2011)
      The extracellular signal-regulated kinase 1 and 2 (ERK 1/2) proteins potently mediate cell proliferation and survival signals via substrate phosphorylation events. Aberrant activation of ERK due to mutations in upstream activators such as B-Raf is a hallmark of a variety of cancers. Thus, inhibition of substrates involved in these mechanisms provides a promising target for anti-cancer therapies. Small molecules designed to interfere with five putative binding sites on ERK2, which are potentially involved in substrate interactions, were developed using computer-aided drug design (CADD) and assessed for their ability to inhibit ERK-mediated signaling events. The inhibitors identified successfully inhibited cell proliferation and survival signals as demonstrated by inhibition of cell cycle progression and/or the induction of apoptosis in cell based assays. Evaluation of the mechanism of action of these ERK-targeted inhibitors revealed inhibitory effects on ERK mediated phosphorylation of p90Rsk-1, which plays a role in cell growth and survival as well as caspase-9, which is involved in the activation of the intrinsic apoptotic pathway resulting in the induction of apoptosis. Additionally, the ERK-targeted inhibitors appeared to enhance chemotherapeutic drugs by inducing a cytostatic effect through selective inhibition of p90Rsk-1 phosphorylation and cyclin D1 expression indicative of a G1-phase arrest in a melanoma model harboring a B-Raf mutation. These studies suggest that selective inhibition of ERK functions is an alternative approach to complete ERK pathway inhibition and can be used to enhance the sensitivity of melanoma cells to chemotherapeutics drugs potentially reducing toxicity to normal cells and the development of drug resistance.