title: Low-molecular-weight MK2 inhibitors: a tough nut to crack!
abstract: The p38 pathway has been at the center of interest for anti-inflammatory drug discovery for many years as it is crucial for the biosynthesis of TNF-α, IL-1β and other mediators. Most of the anti-inflammatory effects of p38 inhibition are mediated through MAPK-activated protein kinase-2 (MK2), a direct downstream target of p38, which makes MK2 a very interesting drug target. Within the last 5 years, several classes of low-molecular-weight MK2 inhibitors were disclosed in the patent and primary literature. Advanced compounds could be optimized to nanomolar potencies and inhibit TNF-α release, as well as the phosphorylation of the MK2 substrate heat-shock protein 27 in cellular assays. This article will review the recent progress in this field and will highlight and discuss the most promising compound series disclosed so far.
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, CH-4056 Basel, Switzerland. achim.schlapbach@novartis.com
authors.forename: Achim
authors.initials: A
authors.lastname: Schlapbach
authors.forename: Christine
authors.initials: C
authors.lastname: Huppertz
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008970:Molecular Weight; D010330:Patents as Topic; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000255:Adenosine Triphosphate; D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2