1443752-50-8Relevant academic research and scientific papers
A cascade screening approach for the identification of Bcr-Abl myristate pocket binders active against wild type and T315I mutant
Radi, Marco,Schneider, Ralf,Fallacara, Anna Lucia,Botta, Lorenzo,Crespan, Emmanuele,Tintori, Cristina,Maga, Giovanni,Kissova, Miroslava,Calgani, Alessia,Richters, André,Musumeci, Franesca,Rauh, Daniel,Schenone, Silvia
, p. 3436 - 3440 (2016)
The major clinical challenge in drug-resistant chronic myelogenous leukemia (CML) is currently represented by the Bcr-Abl T315I mutant, which is unresponsive to treatment with common first and second generation ATP-competitive tyrosine kinase inhibitors (TKIs). Allosteric inhibition of Bcr-Abl represent a new frontier in the fight against resistant leukemia and few candidates have been identified in the last few years. Among these, myristate pocket (MP) binders discovered by Novartis (e.g. GNF2/5) showed promising results, although they proved to be active against the T315I mutant only in combination with first and second generation ATP-competitive inhibitors. Here we used a cascade screening approach based on sequential fluorescence polarization (FP) screening, in silico docking/dynamics studies and kinetic-enzymatic studies to identify novel MP binders. A pyrazolo[3,4-d]pyrimidine derivative (6) has been identified as a promising allosteric inhibitor active on 32D leukemia cell lines (expressing Bcr-Abl WT and T315I) with no need of combination with any ATP-competitive inhibitor.
Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant
Radi, Marco,Tintori, Cristina,Musumeci, Francesca,Brullo, Chiara,Zamperini, Claudio,Dreassi, Elena,Fallacara, Anna Lucia,Vignaroli, Giulia,Crespan, Emmanuele,Zanoli, Samantha,Laurenzana, Ilaria,Filippi, Irene,Maga, Giovanni,Schenone, Silvia,Angelucci, Adriano,Botta, Maurizio
, p. 5382 - 5394 (2013/07/26)
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.
