{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:33:42Z","timestamp":1790631222559,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL176212"],"award-info":[{"award-number":["R01HL176212"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:p>\n                    The Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase (NKA) is a central regulator of cardiac ion homeostasis and a validated target for heart failure. Yet, cardiotonic steroids used in clinical practice are limited by a narrow therapeutic window and pro\u2010arrhythmic effects. Here, we identify Ro 41\u20100960 as a non\u2010steroidal inhibitor of NKA with a distinct mechanistic profile. The compound inhibits NKA activity with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 17.9\u2009\u00b1\u20091.1\u2009\u00b5M for purified enzyme and 10.3\u2009\u00b1\u20091.1\u2009\u00b5M in microsomal preparations. ATP\u2010dependent activity measurements revealed a non\u2010monotonic response in which inhibition was most pronounced at ATP concentrations below 4\u2009mM and diminished at the highest ATP concentrations tested. Docking and molecular dynamics simulations suggest that Ro 41\u20100960 can access both the cardiotonic steroid\u2010binding pocket and the nucleotide\u2010binding site; however, the ATP\u2010dependence data are not consistent with a simple ATP\u2010competitive mechanism. Furthermore, the compound shows only weak inhibition of SERCA (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009&gt;\u2009100\u2009\u00b5M) and does not alter electrophysiological parameters in human iPSC\u2010derived cardiomyocytes at concentrations producing near\u2010maximal NKA inhibition, providing initial evidence of a favorable cardiac safety profile. Together, these findings identify Ro 41\u20100960 as an NKA inhibitor with a distinct chemical scaffold and provide a framework for the development of non\u2010steroidal NKA modulators.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70442","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T01:53:43Z","timestamp":1787968423000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery of Ro 41\u20100960, a Non\u2010Steroidal Inhibitor of the Na\n                    <sup>+<\/sup>\n                    \/K\n                    <sup>+<\/sup>\n                    \u2010ATPase"],"prefix":"10.1002","volume":"21","author":[{"given":"Carlos","family":"Cruz\u2010Cort\u00e9s","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan  Ann Arbor Michigan USA"},{"name":"Center for Arrhythmia Research University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslava","family":"\u0160eflov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Physiology Loyola University Chicago  Maywood Illinois USA"},{"name":"Department of Health and Biomedical Sciences University of Texas Rio Grande Valley  Brownsville Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Guerrero\u2010Serna","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5134-491X","authenticated-orcid":false,"given":"Eric N.","family":"Jimenez\u2010Vazquez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus","family":"Anumonwo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan  Ann Arbor Michigan USA"},{"name":"Center for Arrhythmia Research University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1006-6504","authenticated-orcid":false,"given":"L. 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