Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases

Abstract

ABSTRACTKinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anti-cancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases.KEY CONCEPTSChemical probe: a high-quality small molecule that is potent, selective, and cell-active that meets the following criteria: (1) in vitro biochemical IC50 < 50 nM, (2) ≥ 30-fold selectivity relative to other kinases in a large assay panel such as DiscoverX scanMAX, and (3) cellular activity or target engagement with an IC50 < 1 μMNarrow spectrum: a selectivity threshold that can be defined as potently inhibiting ∼10% or less of all kinases screenedKinome: all human kinasesKinase chemogenomic set (KCGS): publicly-available curated physical library of narrow spectrum and potent kinase inhibitors for which the SGC-UNC has received permission to share the compounds; subsequent releases will increase kinome-wide coverageIlluminating the Druggable Genome (IDG) program: several interconnected projects currently funded by the National Institutes of Health to provide information on historically understudied members within protein families that have provided drug targets; the three main focus areas are kinases, G-protein coupled receptors, and ion channelsIDG kinase: a kinase that was nominated as dark (understudied) by the National Institutes of Health IDG program (curated list found here: https://druggablegenome.net/IDGProteinList); IDG consortium members generate data and resources to aid in the illumination of the function of these kinasesDK tool: a narrow spectrum inhibitor that exhibits a defined selectivity score (S10(1 μM) < 0.05) and cellular target engagement with an IC50 < 1 μM; S10(1 μM) is a measure of selectivity equal to the percentage of screened kinases biochemically inhibited by >90% at 1 μM