The Mystery of EVP4593: Perspectives of the Quinazoline-Derived Compound in the Treatment of Huntington’s Disease and Other Human Pathologies

Abstract

Quinazoline derivatives have various pharmacological activities and are widely used in clinical practice. Here, we reviewed the proposed mechanisms of the physiological activity of the quinazoline derivative EVP4593 and perspectives for its clinical implication. We summarized the accumulated data about EVP4593 and focused on its activities in different models of Huntington’s disease (HD), including patient-specific iPSCs-based neurons. To make a deeper insight into its neuroprotective role in HD treatment, we discussed the ability of EVP4593 to modulate calcium signaling and reduce the level of the huntingtin protein. Moreover, we described possible protective effects of EVP4593 in other pathologies, such as oncology, cardiovascular diseases and parasite invasion. We hope that comprehensive analyses of the molecular mechanisms of EVP4593 activity will allow for the expansion of the scope of the EVP4593 application.

SOCE as a regulator of neuronal activity

“…The reduction in spine density observed in the YAC128 mouse model (expressing the full‐length human huntingtin gene with a 128 glutamine repeat expansion in exon 1) could be rescued by suppression of several proteins involved in the SOCE pathway (STIM1, TRPC1, TRPC6, Orai1 and Orai2) and knocking out TRPC1 in the YAC128 mouse is able to improve its motor performance (Wu et al., 2018). Interestingly, a SOCE inhibitor, the neuroprotective agent EVP4593, is also able to rescue spine loss in the same mouse model, making it an interesting candidate for HD treatment (Grekhnev et al., 2022; Wu et al., 2016). The various, and sometimes opposite, alterations in intracellular Ca 2+ signalling leading to synaptic loss illustrate the complexity and tight regulation of those mechanisms in the brain and that there is no single ‘neuronal SOCE’ but multiple modules depending on localization, function and time.…”