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Two C6\u2010unsubstituted (<jats:bold>1<\/jats:bold> and <jats:bold>2<\/jats:bold>) and eight C6\u2010substituted compounds (<jats:bold>3<\/jats:bold>\u2013<jats:bold>10<\/jats:bold>) were selected and assayed for their effects on the Ba\/F3 cell line transducing the wild\u2010type p210Bcr\u2013Abl construct, which is IM\u2010sensitive, or three of the most common mutations associated with IM resistance in\u2005vivo (T315I, Y253F, and E255K), and driven to drug resistance by saturating doses of IL\u20103 or by the expression of the Bcr\u2013Abl construct coding for the p185 protein of acute lymphoblastic leukemia. Compounds <jats:bold>1<\/jats:bold> and <jats:bold>2<\/jats:bold> were active against all cell lines assayed (LD<jats:sub>50<\/jats:sub> range: 0.7\u20134.3\u2005\u03bc<jats:sc>M<\/jats:sc>), whereas C6\u2010substituted compounds exhibited lower activity (LD<jats:sub>50<\/jats:sub>\u223c8\u2005\u03bc<jats:sc>M<\/jats:sc> for compound <jats:bold>3<\/jats:bold> toward the T315I mutant). Notably, <jats:bold>1<\/jats:bold> and <jats:bold>2<\/jats:bold> were also effective toward the T315I mutation, which is insensitive to dual Src\/Abl inhibitors. The cytotoxic effects of <jats:bold>1<\/jats:bold> and <jats:bold>2<\/jats:bold> on IM\u2010sensitive and IM\u2010resistant Ba\/F3 cells were attributable, at least in part, to their pro\u2010apoptotic activity. Taken together, such findings suggest that C6\u2010unsubstituted pyrazolo[3,4\u2010<jats:italic>d<\/jats:italic>]pyrimidines may represent useful inhibitors to target IM\u2010resistant chronic myeloid leukemia.<\/jats:p>","DOI":"10.1002\/cmdc.200800320","type":"journal-article","created":{"date-parts":[[2008,11,27]],"date-time":"2008-11-27T11:15:10Z","timestamp":1227784510000},"page":"118-126","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["C6\u2010Unsubstituted Pyrazolo[3,4\u2010<i>d<\/i>]pyrimidines Are Dual Src\/Abl Inhibitors Effective against Imatinib Mesylate Resistant Chronic Myeloid Leukemia Cell Lines"],"prefix":"10.1002","volume":"4","author":[{"given":"Maria Alessandra","family":"Santucci","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Corradi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Mancini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabrizio","family":"Manetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Radi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Schenone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Botta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1,5]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(84)90077-1"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.10.3343"},{"key":"e_1_2_6_3_2","doi-asserted-by":"crossref","unstructured":"B.\u2005J.Druker F.Guilhot S.\u2005G.O'Brien I.Gathmann H.Kantarjian N.Gattermann M.\u2005W.Deininger R.\u2005T.Silver J.\u2005M.Goldman R.\u2005M.Stone F.Cervantes A.Hochhaus B.\u2005L.Powell J.\u2005L.Gabrilove P.Rousselot J.Reiffers J.\u2005J.Cornelisse T.Hughes H.Agis T.Fischer G.Verhoef J.Shepherd G.Saglio A.Gratwohl J.\u2005L.Nielsen J.\u2005P.Radich B.Simonsson K.Taylor M.Baccarani C.So L.Letvak R.\u2005A.Larson IRIS investigators N. 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