Repurposing Approved Drugs as Inhibitors of K v 7.1 and Na v 1.8 to Treat Pitt Hopkins Syndrome

Purpose Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K v 7.1 and Na v 1.8 which triggers an increase in after-hyperpolarization and altered firing properties. Methods We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K V 7.1) or HEK293 (Na v 1.8) cells and the HTS used either 86 Rb + efflux (K V 7.1) or a FLIPR assay (Na v 1.8). Results The HTS delivered 55 inhibitors of K v 7.1 (4.2% hit rate) and 93 inhibitors of Na v 1.8 (7.2% hit rate) at a screening concentration of 10 μM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Na v 1.8. Conclusions This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na v 1.8, as there are currently no approved treatments for this rare disorder.