{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T19:25:48Z","timestamp":1773689148157,"version":"3.50.1"},"reference-count":54,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,3,30]],"date-time":"2016-03-30T00:00:00Z","timestamp":1459296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005189","name":"Leukemia & Lymphoma Society","doi-asserted-by":"crossref","award":["SLP-8002-14"],"award-info":[{"award-number":["SLP-8002-14"]}],"id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Leukemia and Lymphoma Society for Canada"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute (NCI)","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"crossref","award":["R01CA178397"],"award-info":[{"award-number":["R01CA178397"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"crossref","award":["P01CA049639"],"award-info":[{"award-number":["P01CA049639"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"crossref","award":["P30CA042014"],"award-info":[{"award-number":["P30CA042014"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2016,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pharmacologic blockade of the activation of signal transducer and activator of transcription\u20053 (STAT3) in tyrosine kinase inhibitor (TKI)\u2010resistant chronic myeloid leukemia (CML) cell lines characterized by kinase\u2010independent resistance was shown to re\u2010sensitize CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. Benzoic acid\u2010 and hydroxamic acid\u2010based STAT3 inhibitors SH\u20104\u2010054 and SH\u20105\u2010007, developed previously in our laboratory, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD\u20101 mice) revealed that both SH\u20104\u2010054 and SH\u20105\u2010007 are susceptible to glutathione conjugation at the <jats:italic>para<\/jats:italic> position of the pentafluorophenyl group via nucleophilic aromatic substitution (S<jats:sub>N<\/jats:sub>Ar). To determine whether the electrophilicity of the pentafluorophenyl sulfonamide could be tempered, an in\u2010depth structure\u2013activity relationship (SAR) study of the SH\u20104\u2010054 scaffold was conducted. These studies revealed that AM\u20101\u2010124, possessing a 2,3,5,6\u2010tetrafluorophenylsulfonamide group, retained STAT3 protein affinity (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=15\u2005\u03bc<jats:sc>m<\/jats:sc>), as well as selectivity over STAT1 (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>&gt;250\u2005\u03bc<jats:sc>m<\/jats:sc>). Moreover, in both hepatocytes and in in\u2005vivo pharmacokinetic studies (CD\u20101 mice), AM\u20101\u2010124 was found to be dramatically more stable than SH\u20104\u2010054 (<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>=1.42\u2005h cf. 10\u2005min, respectively). AM\u20101\u2010124 is a promising STAT3\u2010targeting inhibitor with demonstrated bioavailability, suitable for evaluation in preclinical cancer models.<\/jats:p>","DOI":"10.1002\/cmdc.201600021","type":"journal-article","created":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T17:39:45Z","timestamp":1459445985000},"page":"850-861","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)\u2010Resistant CML Lines While Circumventing Pharmacokinetic Liabilities"],"prefix":"10.1002","volume":"11","author":[{"given":"Ahmed M.","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"},{"name":"Department of Medicinal Chemistry Faculty of Pharmacy Assiut University  Assiut 71515 Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolfo F.","family":"G\u00f3mez\u2010Biagi","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping\u2010Shan","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William L.","family":"Heaton","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute Division of Hematology and Hematologic Malignancies University of Utah  Salt Lake City UT 84112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Sung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna M.","family":"Eiring","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute Division of Hematology and Hematologic Malignancies University of Utah  Salt Lake City UT 84112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadeem A.","family":"Vellore","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute Division of Hematology and Hematologic Malignancies University of Utah  Salt Lake City UT 84112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvin D.","family":"de\u2005Araujo","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan P.","family":"Ball","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew E.","family":"Shouksmith","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ami B.","family":"Patel","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute Division of Hematology and Hematologic Malignancies University of Utah  Salt Lake City UT 84112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael W.","family":"Deininger","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute Division of Hematology and Hematologic Malignancies University of Utah  Salt Lake City UT 84112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"O'Hare","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute Division of Hematology and Hematologic Malignancies University of Utah  Salt Lake City UT 84112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick T.","family":"Gunning","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Toronto Mississauga  Mississauga ON L5L\u20051C6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,3,30]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1056\/NEJM200104053441409","volume":"344","author":"Goldman J. M.","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_6_2_1","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.1200\/JCO.2007.15.8154","volume":"26","author":"de Lavallade H.","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"e_1_2_6_3_1","unstructured":"\u00a0"},{"key":"e_1_2_6_4_2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S1535-6108(02)00096-X","volume":"2","author":"Shah N. P.","year":"2002","journal-title":"Cancer Cell"},{"key":"e_1_2_6_5_2","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1126\/science.1062538","volume":"293","author":"Gorre M. E.","year":"2001","journal-title":"Science"},{"key":"e_1_2_6_6_1","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1021\/ml4003138","volume":"4","author":"Haftchenary S.","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"e_1_2_6_7_1","unstructured":"\u00a0"},{"key":"e_1_2_6_8_2","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.1158\/1535-7163.MCT-08-0314","volume":"7","author":"Bewry N. N.","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"e_1_2_6_9_2","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/leu.2011.325","volume":"26","author":"Traer E.","year":"2012","journal-title":"Leukemia"},{"key":"e_1_2_6_10_1","unstructured":"\u00a0"},{"key":"e_1_2_6_11_2","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/leu.2014.245","volume":"29","author":"Eiring A. M.","year":"2015","journal-title":"Leukemia"},{"key":"e_1_2_6_12_2","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1517\/13543776.2015.1086749","volume":"25","author":"Lai P.-S.","year":"2015","journal-title":"Expert Opin. Ther. Pat."},{"key":"e_1_2_6_13_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0092-8674(00)81959-5","volume":"98","author":"Bromberg J. F.","year":"1999","journal-title":"Cell"},{"key":"e_1_2_6_14_1","unstructured":"\u00a0"},{"key":"e_1_2_6_15_2","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.3324\/haematol.2013.085068","volume":"98","author":"Couronn\u00e9 L.","year":"2013","journal-title":"Haematologica"},{"key":"e_1_2_6_16_2","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1056\/NEJMoa1114885","volume":"366","author":"Koskela H. L. M.","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_6_17_1","unstructured":"\u00a0"},{"key":"e_1_2_6_18_2","doi-asserted-by":"crossref","first-page":"7930","DOI":"10.1074\/jbc.M112.440610","volume":"288","author":"Nallar S. C.","year":"2013","journal-title":"J. Biol. Chem."},{"key":"e_1_2_6_19_2","doi-asserted-by":"crossref","first-page":"45197","DOI":"10.1371\/journal.pone.0045197","volume":"7","author":"Rossa C.","year":"2012","journal-title":"PLoS ONE"},{"key":"e_1_2_6_20_1","doi-asserted-by":"crossref","first-page":"4380","DOI":"10.1158\/0008-5472.CAN-11-0308","volume":"71","author":"Hartman Z. C.","year":"2011","journal-title":"Cancer Res."},{"key":"e_1_2_6_21_1","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1128\/MCB.16.4.1595","volume":"16","author":"Cao X.","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"e_1_2_6_22_1","unstructured":"\u00a0"},{"key":"e_1_2_6_23_2","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1182\/blood.V101.2.690","volume":"101","author":"Donato N. J.","year":"2003","journal-title":"Blood"},{"key":"e_1_2_6_24_2","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1093\/jnci\/djn188","volume":"100","author":"Wu J.","year":"2008","journal-title":"J. Natl. Cancer Inst."},{"key":"e_1_2_6_25_2","doi-asserted-by":"crossref","first-page":"21446","DOI":"10.1074\/jbc.M109.090043","volume":"285","author":"Pene-Dumitrescu T.","year":"2010","journal-title":"J. Biol. Chem."},{"key":"e_1_2_6_26_2","doi-asserted-by":"crossref","first-page":"16870","DOI":"10.1073\/pnas.0606509103","volume":"103","author":"Hu Y.","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_2_6_27_2","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1038\/onc.2009.7","volume":"28","author":"Samanta A. K.","year":"2009","journal-title":"Oncogene"},{"key":"e_1_2_6_28_1","unstructured":"\u00a0"},{"key":"e_1_2_6_29_2","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0960-894X(02)01050-8","volume":"13","author":"Ren Z.","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"e_1_2_6_30_2","unstructured":"J.Turkson P.Gunning(University of Central Florida Research Foundation University of Toronto Mississauga) US Pat. No. US\u20058586749\u2005B2 2011;"},{"key":"e_1_2_6_31_2","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.1021\/ol9012662","volume":"11","author":"Mandal P. K.","year":"2009","journal-title":"Org. Lett."},{"key":"e_1_2_6_32_2","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1021\/jm801491w","volume":"52","author":"Mandal P. K.","year":"2009","journal-title":"J. Med. Chem."},{"key":"e_1_2_6_33_1","unstructured":"S. M.Sebti N. J.Lawrence J.Turkson(H. Lee Moffitt Cancer Center & Research Institute Inc. University of Central Florida Research Foundation) Int. PCT Pub. No. WO\u20052013063504\u2005A1 2013."},{"key":"e_1_2_6_34_1","unstructured":"J. R.Grandis D. E.Johnson P.Leong(University of Pittsburgh\u2014of the Commonwealth System of Higher Education) US Pat. No. US\u20058722640\u2005B2 2006."},{"key":"e_1_2_6_35_1","unstructured":"\u00a0"},{"key":"e_1_2_6_36_2","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1002\/cbic.200900172","volume":"10","author":"Fletcher S.","year":"2009","journal-title":"ChemBioChem"},{"key":"e_1_2_6_37_2","doi-asserted-by":"crossref","first-page":"4700","DOI":"10.1073\/pnas.0409894102","volume":"102","author":"Song H.","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_2_6_38_2","unstructured":"R.Farjo US Pat. No. US\u200520090082470\u2005A1 2009;"},{"key":"e_1_2_6_39_2","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.2337\/diabetes.53.9.2443","volume":"53","author":"Suganami E.","year":"2004","journal-title":"Diabetes"},{"key":"e_1_2_6_40_2","unstructured":"P.Gunning J.Turkson(University of Central Florida Research Foundation Inc. University of Toronto Mississauga) Int. PCT Pub. No. WO\u20052012018868\u2005A1 2012;"},{"key":"e_1_2_6_41_2","doi-asserted-by":"crossref","first-page":"7391","DOI":"10.1073\/pnas.0609757104","volume":"104","author":"Siddiquee K.","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_2_6_42_2","unstructured":"A.Asai K.Matsuno N.Ogo O.Takahashi Y.Masuda A.Muroya Y.Akiyama T.Ashizawa T.Okawara(General Incorporated Association Pharma Valley Project Supporting Organization Pharma Design Inc. Kabushiki Kaisha Yakult Honsha Kumamoto Health Science University Shizuoka Prefecture) US Pat. No. US\u200520120302524\u2005A1 2011."},{"key":"e_1_2_6_43_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nrd2445","volume":"6","author":"Leeson P. D.","year":"2007","journal-title":"Nat. Rev. Drug Discovery"},{"key":"e_1_2_6_44_1","first-page":"55","volume":"7","author":"Earnshaw C.","year":"2010","journal-title":"Chem. World"},{"key":"e_1_2_6_45_1","doi-asserted-by":"crossref","DOI":"10.1002\/9783527645640","volume-title":"Lead Optimizations for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds","author":"Dorwald F. Z.","year":"2012"},{"key":"e_1_2_6_46_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1042\/bj0790516","volume":"79","author":"Booth J.","year":"1961","journal-title":"Biochem. J."},{"key":"e_1_2_6_47_1","unstructured":"\u00a0"},{"key":"e_1_2_6_48_2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.ddtec.2004.10.003","volume":"1","author":"Fern\u00e1ndez C.","year":"2004","journal-title":"Drug Discovery Today"},{"key":"e_1_2_6_49_2","doi-asserted-by":"crossref","first-page":"7696","DOI":"10.1021\/ja034646d","volume":"125","author":"Dalvit C.","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_2_6_50_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ab.2004.03.024","volume":"330","author":"Schust J.","year":"2004","journal-title":"Anal. Biochem."},{"key":"e_1_2_6_51_1","unstructured":"\u00a0"},{"key":"e_1_2_6_52_2","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1158\/0008-5472.CAN-14-3558","volume":"76","author":"Yue P.","year":"2016","journal-title":"Cancer Research"},{"key":"e_1_2_6_53_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1006\/abio.1997.2158","volume":"249","author":"Wu P.","year":"1997","journal-title":"Anal. Biochem."},{"key":"e_1_2_6_54_1","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1126\/science.8197455","volume":"264","author":"Darnell J. E.","year":"1994","journal-title":"Science"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.201600021","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201600021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T16:18:22Z","timestamp":1760285902000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201600021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,30]]},"references-count":54,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,4,19]]}},"alternative-id":["10.1002\/cmdc.201600021"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201600021","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,30]]},"assertion":[{"value":"2016-01-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-03-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}