{"id":6444,"date":"2023-02-17T07:00:56","date_gmt":"2023-02-17T07:00:56","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2020-reengineering-an-antiarrhythmic-drug-using-patient-hipsc-cardiomyocytes-to-improve-therapeutic-potential-and-reduce-toxicity\/"},"modified":"2023-02-17T07:00:57","modified_gmt":"2023-02-17T07:00:57","slug":"2020-reengineering-an-antiarrhythmic-drug-using-patient-hipsc-cardiomyocytes-to-improve-therapeutic-potential-and-reduce-toxicity","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2020-reengineering-an-antiarrhythmic-drug-using-patient-hipsc-cardiomyocytes-to-improve-therapeutic-potential-and-reduce-toxicity\/","title":{"rendered":"2020 &#8211; Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity"},"content":{"rendered":"<p>Modeling cardiac disorders with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes is a new paradigm for preclinical testing of candidate therapeutics. However, disease-relevant physiological assays can be complex, and the use of hiPSC-cardiomyocyte models of congenital disease phenotypes for guiding large-scale screening and medicinal chemistry have not been shown. We report chemical refinement of the antiarrhythmic drug mexiletine via high-throughput screening of hiPSC-CMs derived from patients with the cardiac rhythm disorder long QT syndrome 3 (LQT3) carrying SCN5A sodium channel variants. Using iterative cycles of medicinal chemistry synthesis and testing, we identified drug analogs with increased potency and selectivity for inhibiting late sodium current across a panel of 7 LQT3 sodium channel variants and suppressing arrhythmic activity across multiple genetic and pharmacological hiPSC-CM models of LQT3 with diverse backgrounds. These mexiletine analogs can be exploited as mechanistic probes and for clinical development.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42,44],"resource_type":[75],"application_areas":[50,77],"therapeutic_areas":[54],"target_categories":[61],"target_families":[332],"targets":[93],"resource_keyword":[],"class_list":["post-6444","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","products_tags-patchliner","resource_type-publication","application_areas-ion-channels","application_areas-cell-ipscs-profiling","therapeutic_areas-cardiac-safety-cipa","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-5"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/6444","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=6444"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=6444"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=6444"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=6444"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=6444"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=6444"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=6444"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=6444"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=6444"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}