title: Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant.
abstract: Starting from our in-house library of pyrazolo[3,4-d]pyrimidines, a cross-docking simulation was conducted on Bcr-Abl T315I mutant. Among the selected compounds (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the N1 side chain phenyl ring for the interaction with the T315I mutant. A series of 4-bromo derivatives was thus synthesized and biologically evaluated. Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Francesca
authors.initials: F
authors.lastname: Musumeci
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.forename: Elena
authors.initials: E
authors.lastname: Dreassi
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fallacara
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignaroli
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.forename: Irene
authors.initials: I
authors.lastname: Filippi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl