TY - JOUR
T1 - Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor
T2 - Implications for CML
AU - O'Hare, Thomas
AU - Pollock, Roy
AU - Stoffregen, Eric P.
AU - Keats, Jeffrey A.
AU - Abdullah, Omar M.
AU - Moseson, Erika M.
AU - Rivera, Victor M.
AU - Tang, Hao
AU - Metcalf, Chester A.
AU - Bohacek, Regine S.
AU - Wang, Yihan
AU - Sundaramoorthi, Raji
AU - Shakespeare, William C.
AU - Dalgarno, David
AU - Clackson, Tim
AU - Sawyer, Tomi K.
AU - Deininger, Michael W.
AU - Druker, Brian J.
PY - 2004/10/15
Y1 - 2004/10/15
N2 - The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. The most common imatinib mesylate resistance mechanism involves Bcr-Abl kinase domain mutations that impart varying degrees of drug insensitivity. AP23464, a potent adenosine 5′-triphosphate (ATP)-based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl-transduced Ba/F3 cells (IC50 = 14 nM; imatinib mesylate IC50 = 350 nM). AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl-expressing cells. Biochemical assays with purified glutathione S transferase (GST)-Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate-refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML.
AB - The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. The most common imatinib mesylate resistance mechanism involves Bcr-Abl kinase domain mutations that impart varying degrees of drug insensitivity. AP23464, a potent adenosine 5′-triphosphate (ATP)-based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl-transduced Ba/F3 cells (IC50 = 14 nM; imatinib mesylate IC50 = 350 nM). AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl-expressing cells. Biochemical assays with purified glutathione S transferase (GST)-Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate-refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML.
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U2 - 10.1182/blood-2004-05-1851
DO - 10.1182/blood-2004-05-1851
M3 - Article
C2 - 15256422
AN - SCOPUS:4644368478
SN - 0006-4971
VL - 104
SP - 2532
EP - 2539
JO - Blood
JF - Blood
IS - 8
ER -