{"id":19593,"date":"2026-06-17T10:21:05","date_gmt":"2026-06-17T08:21:05","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=19593"},"modified":"2026-06-17T10:21:05","modified_gmt":"2026-06-17T08:21:05","slug":"2026-highly-selective-small-molecule-kv1-3-inhibitors-bind-to-a-cryptic-pocket-and-stabilize-the-channel-in-a-c-type-inactive-conformation","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2026-highly-selective-small-molecule-kv1-3-inhibitors-bind-to-a-cryptic-pocket-and-stabilize-the-channel-in-a-c-type-inactive-conformation\/","title":{"rendered":"2026 &#8211; Highly selective small molecule Kv1.3 inhibitors bind to a cryptic pocket and stabilize the channel in a C-type inactive conformation"},"content":{"rendered":"<p>The voltage-gated potassium ion channel Kv1.3 is an attractive therapeutic target due to its central role in effector memory T cell activation and autoimmune disease. Achieving subtype-selective inhibition remains challenging due to the high sequence conservation across the Kv1 family and the lack of structural insight into binding for selective small molecule inhibitors. Here, using a ligand-based virtual screening approach seeded from an existing dichlorophenol scaffold, we identify a novel indole-based chemotype as a highly selective small molecule inhibitor of human Kv1.3. Through a combination of site-directed mutagenesis and cryoEM, we map the binding site and elucidate the inhibitory mechanism of both chemotypes. We show that dichlorophenol and indole inhibitors bind to a cryptic pocket in the P-loop adjacent to the selectivity filter, with four ligands occupying this site per Kv1.3 tetramer. Inhibitor binding induces an expansion of the selectivity filter, disrupts key hydrogen bonds, and stabilizes a channel conformation resembling the C-type inactivated state. This inhibitory mechanism is distinct from a pore block and accesses a site previously restricted to peptide-based inhibitors. This study provides the first atomic-level view of small molecule engagement to Kv1.3 and expanding the mechanistic repertoire of voltage-gated ion channel inhibition. Together, our findings enable future comparison of state-dependent inhibition and downstream effector function while establishing a structural framework for the rational development of selective small molecule voltage-gated ion channel therapeutics.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53],"therapeutic_areas":[143],"target_categories":[61],"target_families":[333],"targets":[115],"resource_keyword":[],"class_list":["post-19593","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv1-3"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/19593","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=19593"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=19593"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=19593"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=19593"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=19593"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=19593"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=19593"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=19593"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=19593"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}