title: C6-unsubstituted pyrazolo[3,4-d]pyrimidines are dual Src/Abl inhibitors effective against imatinib mesylate resistant chronic myeloid leukemia cell lines.
abstract: Docking simulations were used to predict the most favorable interaction between the T315I mutated form of Abl (invariably associated with resistance to the tyrosine kinase inhibitor imatinib mesylate, IM) and C6-unsubstituted and substituted pyrazolo[3,4-d]pyrimidines previously found to be dual Src/Abl inhibitors. Two C6-unsubstituted (1 and 2) and eight C6-substituted compounds (3-10) were selected and assayed for their effects on the Ba/F3 cell line transducing the wild-type p210Bcr-Abl construct, which is IM-sensitive, or three of the most common mutations associated with IM resistance in vivo (T315I, Y253F, and E255K), and driven to drug resistance by saturating doses of IL-3 or by the expression of the Bcr-Abl construct coding for the p185 protein of acute lymphoblastic leukemia. Compounds 1 and 2 were active against all cell lines assayed (LD(50) range: 0.7-4.3 microM), whereas C6-substituted compounds exhibited lower activity (LD(50) approximately 8 microM for compound 3 toward the T315I mutant). Notably, 1 and 2 were also effective toward the T315I mutation, which is insensitive to dual Src/Abl inhibitors. The cytotoxic effects of 1 and 2 on IM-sensitive and IM-resistant Ba/F3 cells were attributable, at least in part, to their pro-apoptotic activity. Taken together, such findings suggest that C6-unsubstituted pyrazolo[3,4-d]pyrimidines may represent useful inhibitors to target IM-resistant chronic myeloid leukemia.
authors.affiliation: Istituto di Ematologia e Oncologia Medica "Lorenzo e Ariosto Seràgnoli", Università degli Studi di Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
authors.forename: Valentina
authors.initials: V
authors.lastname: Corradi
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001549:Benzamides; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases