Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat Pitt Hopkins Syndrome

Abstract

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.

Repurposing Pyramax® for the Treatment of Ebola Virus Disease: Additivity of the Lysosomotropic Pyronaridine and Non-Lysosomotropic Artesunate

“…The Assay Central software has been previously described (23)(24)(25)(26)(27)(28)(29)(30)(31)(32) which uses the source code management system Git to gather and store structure-activity datasets collated in Molecular Notebook (Molecular Materials Informatics, Inc. in Montreal, Canada). The output is a high-quality dataset and a Bayesian model using extendedconnectivity fingerprints of maximum diameter 6 (ECFP6) descriptors.…”

Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome

“…Genes involved in pathways including nervous system development, synaptic function and axon development are TCF4 targets (Forrest et al, 2018;Xia et al, 2018). Furthermore, TCF4 regulates the expression of ion channels Na v 1.8 and K v 7.1 (Ekins et al, 2019;Rannals et al, 2016). Recent insights into the mechanisms of activation of TCF4 show that TCF4-dependent transcription in primary neurons is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signalling (Sepp et al, 2017).…”

A Very Large-Scale Bioactivity Comparison of Deep Learning and Multiple Machine Learning Algorithms for Drug Discovery

“…Assay Central TM is proprietary software for curating high-quality datasets, generating Bayesian machine learning models with extended-connectivity fingerprints (ECFP6) generated from the CDK library 56 , and making prospective predictions of potential for bioactivity 1,[51][52][53][57][58][59][60][61][62][63][64] . We have previously described this software in detail 1,[51][52][53][57][58][59][60][61][62][63][64] as well as the interpretation of prediction scores 54,65 , and the metrics generated from internal five-fold cross-validation used to evaluate and compare predictive performances. These metrics include, but are not limited to, ROC score 51 , Cohen's kappa (CK) 66,67 , and Matthew's correlation coefficient (MCC) 68 as described by us previously.…”