Abstract
We recently reported a new class of allosteric inhibitors, exemplified by GNF‐2, that selectively inhibit the proliferation of Bcr‐Abl dependent cells. Here we demonstrate, using selection for resistant Bcr‐Abl clones, site‐directed mutagenesis, affinity chromatography, and steady‐state kinetics, that GNF‐2 inhibits Bcr‐Abl kinase activity by binding to the Abl myristate binding pocket and stabilizes the auto‐inhibited conformation. We demonstrate that the 2‐hydroxyethyl amide analog of GNF‐2, GNF‐5, in combination with ATP‐competitive inhibitors such as nilotinib and dasatinib can overcome the T315I “gatekeeper” mutant of Bcr‐Abl which is resistant to all clinically approved Bcr‐Abl inhibitors. These studies demonstrate that targeting of the Abl myristate binding site can provide an important pharmacological means to overcome mutations that cause resistance to ATP‐competitive inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B165.
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