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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:p>\n                    The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K\n                    <jats:sup>+<\/jats:sup>\n                    channel K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1 with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of &gt;100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1 has been experimentally confirmed as a therapeutic target.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2425494122","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T15:00:36Z","timestamp":1745852436000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K\n                    <sub>Ca<\/sub>\n                    3.1"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6089-4745","authenticated-orcid":false,"given":"Seow Theng","family":"Ong","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Woo","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"Nasburg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Ramanishka","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6389-252X","authenticated-orcid":false,"given":"Xuan Rui","family":"Ng","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Shee Min","family":"Goay","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1422-7041","authenticated-orcid":false,"given":"Hai M.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latika","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikrant","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0433-6367","authenticated-orcid":false,"given":"Alicia","family":"Rivera","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center","place":["Boston"]},{"name":"Department of Medicine, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8248-6793","authenticated-orcid":false,"given":"M. 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W. Nam M. Zhang Data from \u201cCryo-EM structure of the human KCa3.1\/calmodulin channel in complex with Ca2+ and 1 4-dihydropyridine (DHP-103).\u201d Protein Data Bank. https:\/\/doi.org\/10.2210\/pdb9ED1\/pdb. 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