Brain-penetrant kinase inhibitors targeting Alzheimer's and related dementias

Alzheimer’s dementia (AD) affects nearly 6 million US patients and costs > $250B/year. No therapies slow its devastating course. We have discovered a root cause of neuronal cell death in disease-relevant regions of autopsied AD brains: inflammation spatially coincident with genomically-encoded cytoplasmic double stranded RNA (cdsRNA). In mouse models, genomically encoded cdsRNA triggers neuroinflammation and neuronal death in a non-cell autonomous mechanism. We recapitulated this cascade of cdsRNA, neuroinflammation, and neuronal death in cultured differentiated human neural cells. This proposal focuses on small molecule kinases inhibitors that we have shown to block this cascade of cdsRNA-mediated neuronal death. Some of the active molecules are annotated as JAK inhibitors, but this class of FDA approved compounds is known to have complex poly-pharmacology and safety concerns. Moreover, a panel of JAK inhibitors heterogeneously rescued human neural cell death in culture. In our genome-wide CRISPR/Cas9 screen one protein kinase was the only JAK family member that conferred rescue when knocked out. In our pilot QFASTR award, we identified another protein kinase as an “off-target” kinase that was preferentially bound by neuroprotective JAK inhibitors relative to inactive JAK inhibitors. Moreover, we demonstrated that inhibitors of the two kinases rescue the neuronal cell death in two human neural cell lines. Here, we propose to focus on one of these protein kinases, validate it as a target by generating knockout human neural cell line using CRISPR/Cas9, and to proceed with SAR and in silico docking to generate leads that target the kinase with brain penetrant properties. Candidate leads that rescue in our phenotypic assay will be tested for brain penetration in our in vivo mouse model system. Successful execution will generate leads for further optimization.