Targeting Human CNS Protein Kinases Involved in Disease Progression: Case Study of an Isoform Selective and Orally Bioavailable S/T PKI Candidate That Attenuates Synaptic and Cognitive Dysfunctions

Abstract

Diverse central nervous system (CNS) disorders display common pathophysiology progression mechanisms that include potential molecular target candidates. Efforts to develop disease‐modifying therapeutics reflect the increasing appreciation of these core mechanisms. Major challenges include identification of disease progression time windows amenable to intervention, the linkage of disease related phenotypes to druggable molecular targets, and the need for pharmacodynamic (PD) end points related to drug target engagement or efficacy. In this regard, clinical and animal model data have generated wide‐ranging interest in stress related pathways in neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD), amyotropic lateral sclerosis (ALS), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and autism spectrum disorders (ASD). A stress related target with extensive linkage to CNS disease and pathophysiology progression is the serine/threonine protein kinase p38αMAPK. MW150 is a promising, novel small molecule, isoform selective, p38αMAPK inhibitor. MW150 is a best‐in‐class deliverable from a third generation medicinal chemistry refinement program that focused on pharmacological optimization with retention of target affinity and specificity.1,2 MW150 emerged from diversification done in the context of our CNS protein kinase inhibitor discovery platform1–4. Structure assisted chemical diversification began with a molecular fragment from our previous non‐kinase CNS campaign that delivered a safe experimental therapeutic now in clinical trial stage. Several highly selective, blood‐brain barrier penetrant p38αMAPK inhibitors emerged from the campaign1,2. Large scale, hierarchal kinome‐wide screens documented kinase selectivity. Large scale functional GPCR screens for agonist or antagonist activity demonstrated a lack of cross over to this prevailing major CNS drug target class. Endogenous p38αMAPK engagement was evidenced by a concentration dependent inhibition of phosphorylation of the relevant endogeneous kinase substrate. The novel p38αMAPK inhibitors also attenuate in a concentration dependent manner the downstream production of PD markers linked to in vivo pathophysiology progression. Specificity is further supported by lack of efficacy and engagement of PD end points in a drug resistant mouse model. Initial preclinical proof‐of‐concept studies were done in mouse models with disease relevant or age related synaptic and cognitive dysfunction where dose dependent efficacy was observed. Additional models characterized by p38αMAPK mediated pathology changes are also being tested. MW150 shows in vivo modulation of quantitative PD end points that are related to the mechanism of disease progression and efficacy as well as drug action. A GMP compatible production scheme has been developed and drug production is in process. Overall, MW150 represents an addition to the compendium of novel candidates targeting pathophysiology progression related to human CNS disease progression.Support or Funding InformationSupported in part by NIH awards U01 AG043415 and U01 AG050636 and support by the ADDF.