Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration

Neurodegenerative diseases affect a rapidly growing number of the aging population globally. These conditions have proven extremely difficult to treat due to our limited understanding of their mechanisms, but they are characterized by protein aggregation, inflammation, lysosomal dysfunction, and neuronal death. Phenotypic drug screens promise to deliver “target agnostic” therapies without being hypothesis limited as with target-based screens. Here, we describe our work to develop and characterize small molecule C381. The compound is a benzyl urea derivative containing a piperidine ring. It is brain penetrant with a ClogP of 3.3 and an oral bioavailability of 48%. We tested the compound in Progranulin(−/−) mice (a model of lysosomal storage disease and frontotemporal dementia) and the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD) where it showed prominent antiinflammatory and neuroprotective effects. In the PD model, C381 restored cognitive function and rescued dopaminergic neuron loss. To identify the target, we performed a genome-wide CRISPR interference (CRISPRi) drug target identification screen, which implicated the lysosome. After validating the screen results with individual knockdown cell lines, follow-up functional studies revealed that C381 physically targets the lysosome, promotes lysosomal acidification, increases breakdown of lysosomal cargo, and improves lysosome resilience to damage. As a first-in-class compound capable of restoring lysosomal function, C381 has the potential both as a therapeutic and as a research compound to better understand lysosomal contributions to disease progression. Together, our work has produced a promising drug candidate for the treatment of neurodegenerative diseases marked by lysosomal dysfunction.