期刊
CELL STEM CELL
卷 27, 期 5, 页码 813-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2020.08.003
关键词
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资金
- National Institutes of Health [NIH R01HL113601, R01HL130840, R01HL141358, P01HL141084, R21HL141019, U01 HL131914, R01HL123483]
- American Heart Association [9SFRN34820006]
- California Institute for Regenerative Medicine (CIRM grant) [TR4-06857]
- NIH at the Sanford-Burnham-Prebys Medical Discovery Institute [P30CA030199]
- Stanford Cardiovascular Institute
- Stanford School of Medicine funds
- European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant [708459]
- Joan and Sanford Weill Scholarship Endowment
- Marie Curie Actions (MSCA) [708459] Funding Source: Marie Curie Actions (MSCA)
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.
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