Repurposing Approved Drugs as Inhibitors of K7.1 and Na1.8 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 K7.1 and Na1.8 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 (K7.1) or HEK293 (Na1.8) cells and the HTS used either Rb efflux (K7.1) or a FLIPR assay (Na1.8).

Results: The HTS delivered 55 inhibitors of K7.1 (4.2% hit rate) and 93 inhibitors of Na1.8 (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 Na1.8.

Conclusions: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na1.8, as there are currently no approved treatments for this rare disorder.