{"id":19591,"date":"2026-06-17T10:12:38","date_gmt":"2026-06-17T08:12:38","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=19591"},"modified":"2026-06-17T10:12:38","modified_gmt":"2026-06-17T08:12:38","slug":"2026-discovery-of-kv3-1-channel-inhibitors-reveals-vu0521426-as-a-state-dependent-inactivator-preferentially-active-against-pathogenic-gain-of-function-mutants","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2026-discovery-of-kv3-1-channel-inhibitors-reveals-vu0521426-as-a-state-dependent-inactivator-preferentially-active-against-pathogenic-gain-of-function-mutants\/","title":{"rendered":"2026 &#8211; Discovery of Kv3.1 channel inhibitors reveals VU0521426 as a state-dependent inactivator preferentially active against pathogenic gain-of-function mutants"},"content":{"rendered":"<p>Kv3.1 voltage-gated potassium channels play a critical role in regulating neuronal excitability, and dysregulation driven by gain-of-function (GoF) mutations has been implicated in neurological disease. Although Kv3.1 potentiators have been at the forefront of drug development as a means to enhance neuronal firing, progress towards small-molecule Kv3.1 inhibitors has been limited. Here, we address this gap with the discovery of novel and structurally diverse Kv3.1 channel inhibitors identified through a high-throughput screening of over 50,000 compounds. Among these, VU426 emerged as the most potent compound with an IC<sub>50<\/sub>\u00a0of 4.3 \u03bcM. VU426 induces pronounced, state-dependent inhibition of outward K<sup>+<\/sup>\u00a0current with sustained depolarization, indicating stabilization of an inactivated channel conformation accessed from the open state. Functional characterization of four GoF mutations (V425M, M430I, V432M, and V434L) in the S6 pore lining domain demonstrated that VU426 exhibits 1.5- to 5-fold enhanced potency toward pathogenic GoF Kv3.1 mutants relative to wild-type channels. Automated patch clamp electrophysiological studies revealed that V432M and V434L mutations embedded deep in the S6 domain had the greatest sensitivity to VU426. Despite its potency, VU426 exhibited limited selectivity for Kv3.1 over related Kv channels. Together, these findings identify novel Kv3.1 inhibitors and highlight a pharmacological strategy for targeting clinically identified pathogenic variants.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[55,143],"target_categories":[61],"target_families":[333],"targets":[276],"resource_keyword":[],"class_list":["post-19591","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-cns","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv3-1"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/19591","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=19591"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=19591"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=19591"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=19591"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=19591"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=19591"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=19591"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=19591"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=19591"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}