Small molecule inhibitors of TrkB Signaling

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a common and commonly devastating form of human epilepsy that lacks preventive or disease modifying therapy. An estimated 30% suffer recurrent seizures despite symptomatic treatment with anticonvulsants. One cause of TLE is status epilepticus (SE). Defining the molecular mechanisms by which SE induces TLE promises to identify molecular targets for therapies. We therefore conducted extensive target validation experiments which revealed TrkB-PLCγ1 as a druggable molecular target that can prevent TLE in adult mice. The goal of our drug discovery program is to develop small molecule inhibitors for TrkB-PLCγ1 signaling to treat TLE. With the support of Blueprint Neurotherapeutics Network (BPN), we identified multiple compounds within distinct series with demonstrated in vivo efficacy for inhibition of TrkB-PLCγ1 signaling in mouse brain. Our Specific Aims are to benchmark, expand, and optimize novel small molecule inhibitors of TrkB-PLCγ1 signaling. Successful completion of the work proposed will identify a leading series for entry to the Discovery Phase of BPN program.