In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B165-B165
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-09-B165
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2009
ZDB Id:
2062135-8
SSG:
12
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