Selective targeting of the αC and DFG-out pocket in p38 MAPK

Abstract

The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into backpocket interactions that are not addressed in SR-318, and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.

FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion

“…To further show that FANCC regulated microglial pyroptosis via a p38/NLRP3 dependent pathway, the p38 inhibitor BIRB 796 and an NLRP3 inhibitor glyburide were employed to induce p38/NLRP3 signaling blockade, respectively [ 25 , 26 ]. WB showed that OE-FANCC decreased p-p38 and NLRP3 protein levels, which were further reduced after treatment with BIRB 796 (Fig.…”

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

“…Replacement of the terminal primary amide with the N -ethyl- N -methyl tertiary amide led to a selective type-II inhibitor of p38α despite weaker potency (IC 50 = 14 nM). It was tested against a 468-kinase panel at 1 µM concentration and inhibited only thirteen kinases including p38α and p38β (98.5% and 96.6% inhibition, respectively) [ 71 ].…”

The p38 MAPK Inhibitors and Their Role in Inflammatory Diseases

“…In addition, 137 induced an antiinflammatory response by blocking TNF-α release in whole blood and displayed a high metabolic stability. [45] Compound 137 was tested against a panel of 468 kinases and kinase mutants. It showed favorable selectivity, with only seven detected off-targets: DDR1/2, ZAK, ABL1, STK11, MAP3 K4 and EPHA1.…”

“…Compound 137 inhibited p38α and p38β in cellulo with low nanomolar potencies, whereas only micromolar potencies were determined for the off-targets. [45] Kaieda et al (2018) realized an extensive SAR analysis of imidazo [1,2-b]pyridazine derivatives, discovering the compound 10a, which have a type I mode of inhibition and strongly inhibited p38 (IC 50 : 4,4 nM) and the production of TNF-α in human THP-1 cells. The in vitro structural analysis of the metabolites of compound 10a resulted in the discovery of pyridine N-oxide 15a (IC 50 : 5.4 nM) which exhibited a dramatically improved metabolic stability in human liver microsomes.…”