Stephen J. O'Keefe

TL;DR: It is reported that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner.

TL;DR: These data provide the first demonstration in vivo thatactivation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism‐based toxicities associated with FK‐506 and CsA by demonstrating that these drugs can inhibit the calcineurin‐dependent activation of a virtually ubiquitous transcription factor.

TL;DR: 48, a potent and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

TL;DR: It is demonstrated in vivo that at concentrations consistent with its IC50 as a cytokine inhibitor, SB203580 can inhibit stimulus-induced phosphorylation of p38 at the Thr-Gly-Tyr activation motif.

TL;DR: Comparing the crystal structures of p38 bound to four different compounds shows that binding of the more specific molecules is characterized by a peptide flip between Met109 and Gly110, which confirms that the selectivity of quinazolinones and pyridol-pyrimidines results from the presence of a glycine in position 110.