Qiang Ding

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Expanding the diversity of purine libraries

Abstract In recent years, there has been a resurgence of interest in the synthesis of purine derivatives due to the discovery of purine-derived ligands for a variety of nucleotide dependent enzymes. The majority of chemistry has focused on substitution of the purine core structure by alkylation at N9 and nucleophilic–aromatic substitution reactions at C2 and C6. Here we report the syntheses of aryl, N -aryl, O -aryl substituted purine libraries by the palladium-mediated coupling of boronic acids, anilines or phenols at the C2 position, and copper(II)-mediated N -arylation with boronic acids at the N9 position. The chemistry described here greatly expands our ability to introduce different functionality and create new purine scaffolds.

Expanding the diversity of allosteric bcr-abl inhibitors.

Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure−activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl−compound 1 cocrystal. We elucidate the structure−activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.