PAMAPIMOD

This is a clinical candidate p38 inhibitor that has been demonstrated to be effective in an in vivo model of acute inflammation, such as rheumatoid arthritis. However, the results need to be carefully evaluated, as the compound inhibits other kinases related to inflammatory diseases, such as C-Jun N-terminal kinases (MAPK8, MAPK9, and MAPK10), in vitro, and off-target activity has not yet been assessed in cells. SR-318, which was developed by the SGC, could be used as an orthogonal probe. Compared to Pamapimod (type I inhibitor), it targets the inactive conformation of MAPK14 (type II inhibitor). SR-318 is potent and highly selective in cells, but its efficiency in vivo has not yet been evaluated.

Pamapimod (compound 2b) is a highly potent, isoform-selective small-molecule inhibitor of p38α (MAPK14), a serine/threonine kinase central to inflammatory signaling pathways. Originally developed for the treatment of autoimmune and inflammatory disorders, Pamapimod binds p38α with nanomolar affinity (IC₅₀ = 14 nM) and exhibits preferential inhibition of the p38α and p38β isoforms, with minimal activity against the γ and δ isoforms. This selectivity profile offers a focused approach to dissecting p38α-driven biology while avoiding broader inhibition of the entire MAPK family. Pamapimod has been shown to effectively block downstream signaling in cellular models, including the inhibition of pro-inflammatory cytokine production such as TNF-α and IL-1β in LPS-stimulated THP-1 cells and human whole blood. These findings are supported by in vivo pharmacological studies, where Pamapimod reduced cytokine levels and modulated inflammatory phenotypes. The compound also demonstrated high oral bioavailability (62–80%), moderate-to-high systemic half-life (∼4 hours in rodents, >9 hours in non-human primates), and favorable metabolic stability, making it suitable for use in translational models. Despite these strengths, Pamapimod does not meet the criteria for a best-in-class chemical probe. While it exhibits submicromolar binding to only 7 of over 300 kinases screened, a full kinome-wide selectivity profile is not publicly available, and no structurally related inactive analog is provided to control for off-target effects. These limitations restrict its use in mechanistic or chemogenomic studies where high target specificity and matched controls are essential. Pamapimod should be classified as a potent, selective, and clinically validated pharmacological inhibitor of p38α, with extensive supporting data from crystallography, SAR, and in vivo pharmacology. It is particularly valuable in contexts requiring in vivo validation, disease modeling, or pharmacodynamic studies of p38α modulation. However, researchers aiming to delineate precise kinase-dependent mechanisms should consider more selective and well-characterized probe molecules accompanied by appropriate negative controls.