{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:57:43Z","timestamp":1792634263112,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":1981,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2003,9]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug\u2010discovery effort, we have synthesized and characterized Z\u2010VD\u2010fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC<jats:sub>50<\/jats:sub> values ranging from 5 to 20 n<jats:sc>M<\/jats:sc>. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC<jats:sub>50<\/jats:sub> values &gt;10 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide\u2010 and tripeptide\u2010based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>MX1013 is more aqueous soluble than tripeptide\u2010based caspase inhibitors such as Z\u2010VAD\u2010fmk.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>At a dose of 1 mg kg<jats:sup>\u22121<\/jats:sup> i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti\u2010Fas mouse\u2010liver apoptosis model, a widely used model of liver failure.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>At a dose of 20 mg kg<jats:sup>\u22121<\/jats:sup> (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia\/reperfusion injury.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>At a dose of 20 mg kg<jats:sup>\u22121<\/jats:sup> (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Based on these studies, we conclude that MX1013, a dipeptide pan\u2010caspase inhibitor, has a good combination of <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2003) <jats:bold>140<\/jats:bold>, 402\u2013412. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705450\">10.1038\/sj.bjp.0705450<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705450","type":"journal-article","created":{"date-parts":[[2003,9,18]],"date-time":"2003-09-18T19:58:43Z","timestamp":1063915123000},"page":"402-412","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["MX1013, a dipeptide caspase inhibitor with potent <i>in vivo<\/i> antiapoptotic activity"],"prefix":"10.1111","volume":"140","author":[{"given":"Wu","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Guastella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Cheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhtam","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Woodward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailaja","family":"Kasibhatla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Drewe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui Xiong","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.58.1.26"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(98)01341-3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/6514"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.2.253"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.1161"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199803000-00002"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0741-5214(99)70115-1"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb09255.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03402071"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202931200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.5.2007"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.82.11.1111"},{"key":"e_1_2_7_14_1","first-page":"811","article-title":"Characterization of the caspase inhibitor IDN\u20101965 in a model of apoptosis\u2010associated liver injury","volume":"297","author":"HOGLEN N.C.","year":"2001","journal-title":"J. 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