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Title: Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant
Authors: Botta, Maurizio 
Tintori, Cristina
Musumeci, F.
Brullo, C.
Zamperini, Claudio
Dreassi, Elena 
Fallacara, ANNA LUCIA
Vignaroli, Giulia
Crespan, E.
Zanoli, S.
Laurenzana, Ilaria
Filippi, I.
Maga, G.
Schenone, S.
Angelucci, A.
Botta, Maurizio 
Issue Date: 2013
Project: None 
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.
ISSN: 0022-2623
DOI: 10.1021/jm400233w
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