Structurally Unique Inhibitors of Human Mitogen-Activated Protein Kinase Phosphatase-1 Identified in a Pyrrole Carboxamide Library

Abstract

Body size is significantly correlated with number of vertebrae (pleomerism) in multiple vertebrate lineages, indicating that change in number of body segments produced during somitogenesis is an important factor in evolutionary change in body size, but the role of segmentation in the evolution of extreme sizes, including gigantism, has not been examined. We explored the relationship between body size and vertebral count in basal snakes that exhibit gigantism. Boids, pythonids and the typhlopid genera, Typhlops and Rhinotyphlops, possess a positive relationship between body size and vertebral count, confirming the importance of pleomerism; however, giant taxa possessed fewer than expected vertebrae, indicating that a separate process underlies the evolution of gigantism in snakes. The lack of correlation between body size and vertebral number in giant taxa demonstrates dissociation of segment production in early development from somatic growth during maturation, indicating that gigantism is achieved by modifying development at a different stage from that normally selected for changes in body size.

Aging Mouse Hearts Are Refractory to Infarct Size Reduction With Post-Conditioning

“…Given the nonspecific actions of orthovanadate (including inhibition of protein tyrosine phosphatases and adenosine triphosphatases [31][32][33]), these data do not constitute proof of a cause-and-effect relationship. Indeed, definitive resolution of this concept is hampered by the current lack of pharmacological and molecular agents capable of selectively targeting MKPs (34). In addition, our results do not exclude the possibility that age-related alterations in other signaling molecules (including, for example, attenuated expression of STAT 3 [9]) may contribute to the failure of stuttered reflow to limit infarct size in hearts from aging mice.…”

The role and target potential of protein tyrosine phosphatases in cancer

“…Low molecular weight compounds with MKP-1 inhibitory activities have been reported with in vitro IC 50 in the low micromolar range [96]. Consistent with targeting MKP-1, some of the inhibitory compounds were capable of inducing cancer cell death in culture and sensitizing cancer cells to chemotherapeutics [96].…”

“…Consistent with targeting MKP-1, some of the inhibitory compounds were capable of inducing cancer cell death in culture and sensitizing cancer cells to chemotherapeutics [96]. Further improvement of potency and selectivity will be needed to evaluate preclinical antitumor activity in animal models and to assess the significance of MKP-1 in antitumor action.…”

A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells

“…Such compounds might not only be useful for improving the efficacy of antineoplastic agents under conditions of high MKP-1 expression but would also be valuable to probe the biochemical substrates and functionality of MKP-1. Although we have identified several pharmacophores with in vitro activity against MKP-1 (15 -17), few have cellular activities associated with MKP-1 inhibition (17,18). Currently, the most popular approach to identifying potential phosphatase inhibitors are in vitro assays using recombinant enzymes and smallmolecule synthetic substrates, such as p -nitrophenyl phosphate or O-methyl fluorescein phosphate.…”