A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction

Abstract

The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clinical trials.

Involvement of p38 MAPK in Synaptic Function and Dysfunction

“…In addition, several inhibitors of p38α MAPK were effective in ameliorating the behavioral deficit in a mouse model of tau-related neurodegeneration, the reversible transgenic (rTg4510) mouse model. These mice overexpressed a human, mutant tau form (P301L) and developed age-related cognitive impairment, neurofibrillary tangles, and neuronal loss [73]. Overall, this evidence favors the hypothesis that p38 MAPK and, in particular, the α isoform, contribute to different pathological process, and therefore represents a promising therapeutic target for the treatment of AD [11,44].…”

“…The CNS exposure limitation is most often linked to the molecular properties of the small molecule drugs [78]. However, this is a barrier that can be addressed through medicinal chemistry refinement [73,79].…”

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

“…Next, we investigated whether p38a MAPK activation contributes to p53 S18 phosphorylation in SMA motor neurons by taking advantage of the established permeability of MW150 (Roy et al, 2019) in the CNS. We treated SMA mice daily by intraperitoneal (i.p.)…”

“…We treated SMA mice daily by intraperitoneal (i.p.) injection with either saline or 5 mg/kg of MW150-a dose previously demonstrated to effectively inhibit p38a MAPK in the CNS and to improve the phenotype of mouse models of neurological disease (Robson et al, 2018;Roy et al, 2015Roy et al, , 2019Rutigliano et al, 2018;Zhou et al, 2017). Importantly, MW150 treatment robustly decreased the levels of p53 S18 phosphorylation but not the induction of p53 in vulnerable L5 MMC SMA motor neurons relative to vehicle-treated SMA mice at P11 ( Figures 5E-5H), directly linking p38a MAPK activation to the phosphorylation of p53 S18 in SMA motor neurons.…”

A selective p38 MAPK inhibitor alleviates neuropathology and cognitive impairment by modulating microglia function in 5XFAD mouse

“…Most studies have been performed using induced neurodegenerative in vivo models or indirect p38 MAPK inhibitors. One group has recently reported therapeutic effects in 12-month-old APP/PS1 mouse using the direct inhibitor, MW150 [50,51]. In this study, we exhibited, the therapeutic effect of a direct and selective p38 MAPK inhibitor NJK14047 and investigated its mode of action in 9-month-old 5XFAD mice.…”