{"id":129,"date":"2013-02-26T05:56:33","date_gmt":"2013-02-25T21:56:33","guid":{"rendered":"http:\/\/www.huanglab.org.cn\/wordpress\/?p=129"},"modified":"2013-06-09T10:59:24","modified_gmt":"2013-06-09T02:59:24","slug":"a-new-target-for-an-old-drug-identifying-mitoxantrone-as-a-nanomolar-inhibitor-of-pim1-kinase-via-kinome-wide-selectivity-modeling","status":"publish","type":"post","link":"https:\/\/www.huanglab.org.cn\/wordpress\/?p=129","title":{"rendered":"A New Target for An Old Drug: Identifying Mitoxantrone as a Nanomolar Inhibitor of PIM1 Kinase via Kinome-wide Selectivity Modeling"},"content":{"rendered":"<p><a href=\"http:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2013\/03\/xbpaper.jpg\"><img loading=\"lazy\" class=\"alignnone size-medium wp-image-190\" alt=\"xbpaper\" src=\"http:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2013\/03\/xbpaper-300x225.jpg\" width=\"300\" height=\"225\" srcset=\"https:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2013\/03\/xbpaper-300x225.jpg 300w, https:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2013\/03\/xbpaper-1024x768.jpg 1024w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><\/a><\/p>\n<p>Xiaobo Wan,\u2020,\u2021\u00a7 Wei Zhang,\u2021\u00a7 Li Li,\u2021 Yuting Xie,\u2021 Wei Li\u2020,\u2021 and Niu Huang*,\u2021,\u2020<br \/>\n\u2020 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing, China<br \/>\n\u2021 National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China<br \/>\n\u00a7These authors equally contributed to this work.<\/p>\n<p>* To whom correspondence should be addressed. Phone: 86-10-80720645. Fax: 86-10-80720813.<br \/>\nE-mail: huangniu@nibs.ac.cn<\/p>\n<p>ABSTRACT: The rational design of selective kinase inhibitors remains a great challenge. Here<br \/>\nwe describe a physics-based approach to computationally modeling the kinase inhibitor<br \/>\nselectivity profile. We retrospectively assessed this protocol by computing the binding profiles of<br \/>\n17 well-known kinase inhibitors against 143 kinases. Next, we predicted the binding profile of<br \/>\nthe chemotherapy drug mitoxantrone, and chose the predicted top five kinase targets for in vitro<br \/>\nkinase assays. Remarkably, mitoxantrone was shown to possess low nanomolar inhibitory<br \/>\nactivity against PIM1 kinase and to inhibit the PIM1-mediated phosphorylation in cancer cells.<br \/>\nWe further determined the crystal complex structure of PIM1 bound with mitoxantrone, which<br \/>\nreveals the structural and mechanistic basis for a novel mode of PIM1 inhibition. Although<br \/>\nmitoxantrone\u2019s mechanism of action had been originally thought to act through DNA<br \/>\nintercalation and type II topoisomerase inhibition, we hypothesize that PIM1 kinase inhibition<br \/>\nmight also contribute to mitoxantrone\u2019s therapeutic efficacy and specificity.<\/p>\n<p><a title=\"Full Article\" href=\"http:\/\/pubs.acs.org\/doi\/abs\/10.1021\/jm400045y\" target=\"_blank\">Full Article<br \/>\n<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Xiaobo Wan,\u2020,\u2021\u00a7 Wei Zhang,\u2021\u00a7 Li Li,\u2021 Yuting Xie,\u2021 Wei Li\u2020,\u2021 and Niu Huang*,\u2021,\u2020 \u2020 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing, China \u2021 National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China \u00a7These authors equally contributed to this [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"ngg_post_thumbnail":0},"categories":[],"tags":[],"_links":{"self":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/129"}],"collection":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=129"}],"version-history":[{"count":8,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/129\/revisions"}],"predecessor-version":[{"id":366,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/129\/revisions\/366"}],"wp:attachment":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=129"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=129"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=129"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}