Ganaxolone, an approved therapy for CDKL5-deficiency disorder, is an inhibitor of PTP1B.

CDKL5-deficiency disorder or CDD, which results in intellectual disability, speech, and motor deficits, and seizures that can start as early as 6 weeks after birth, is caused by de novo mutations in the CDKL5 gene. In early 2022, the FDA approved ganaxolone (Commercial name: Ztalmy) for the treatment of seizures in CDD patients 2 years and older. Ganaxolone has been reported to act as a GABAA receptor agonist that helps reduce neuronal excitability; however, based on its chemical structure, we hypothesized that ganaxolone may also act as a PTP1B inhibitor. We observed that ganaxalone was able to inhibit PTP1B activity both in an in vitro assay of enzyme activity and in different cell models, with similar potency to known inhibitors of PTP1B, including MSI-1436, which has a similar chemical structure. Additionally, inhibition of PTP1B in differentiating SH-SY5Y cells increased TRKB/BDNF signaling. This effect was prominent in CDKL5-KO cells, which have increased PTP1B expression. In these cells, inhibition of PTP1B not only brought BDNF signaling to levels similar to those of WT cells but also restored cellular morphology. Our results suggest that, like in Rett syndrome, targeting PTP1B may be a beneficial therapeutic strategy for CDD.