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.
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. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 26:15(2016), pp. 3436-3440. [10.1016/j.bmcl.2016.06.051]
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