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A cascade screening approach for the identification of Bcr-Abl myristate pocket binders active against wild type and T315I mutant.

Autori

Radi M, Schneider R, Fallacara AL, Botta L, Crespan E, Tintori C, Maga G, Kissova M, Calgani A, Richters A, Musumeci F, Rauh D, Schenone S.

Riferimenti

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 26(15) 3436-3440, 2016

Autori CNR

CRESPAN, MAGA

Moduli

Abstract

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.

Link all articolo

http://www.sciencedirect.com/science/article/pii/S0960894X1630662X

Parole Chiave

Note

10.1016/j.bmcl.2016.06.051

Indietro


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