Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl

被引:1169
作者
Weisberg, E
Manley, PW
Breitenstein, W
Brüggen, J
Cowan-Jacob, SW
Ray, A
Huntly, B
Fabbro, D
Fendrich, G
Hall-Meyers, E
Kung, AL
Mestan, J
Daley, GQ
Callahan, L
Catley, L
Cavazza, C
Mohammed, A
Neuberg, D
Wright, RD
Gilliland, DG
Griffin, JD [1 ]
机构
[1] Dana Farber Canc Inst, Boston, MA 02115 USA
[2] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland
[3] Brigham & Womens Hosp, Boston, MA 02115 USA
[4] Childrens Hosp, Boston, MA 02115 USA
关键词
D O I
10.1016/j.ccr.2005.01.007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 < 30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant betacr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CIVIL and Ph+ ALL.
引用
收藏
页码:129 / 141
页数:13
相关论文
共 63 条
[1]   Inhibition of FLT3 in MLL: Validation of a therapeutic target identified by gene expression based classification [J].
Armstrong, SA ;
Kung, AL ;
Mabon, ME ;
Silverman, LB ;
Stam, RW ;
Den Boer, ML ;
Pieters, R ;
Kersey, JH ;
Sallan, SE ;
Fletcher, JA ;
Golub, TR ;
Griffin, JD ;
Korsmeyer, SJ .
CANCER CELL, 2003, 3 (02) :173-183
[2]   Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL [J].
Azam, M ;
Latek, RR ;
Daley, GQ .
CELL, 2003, 112 (06) :831-843
[3]   Mutation in the ATP-binding site of BCR-ABL in a patient with chronic myeloid leukaemia with increasing resistance to STI571 [J].
Barthe, C ;
Gharbi, MJ ;
Lagarde, V ;
Chollet, C ;
Cony-Makhoul, P ;
Reiffers, J ;
Goldman, JM ;
Melo, JV ;
Mahon, FX .
BRITISH JOURNAL OF HAEMATOLOGY, 2002, 119 (01) :109-111
[4]  
BEDI A, 1994, BLOOD, V83, P2038
[5]   High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance [J].
Branford, S ;
Rudzki, Z ;
Walsh, S ;
Grigg, A ;
Arthur, C ;
Taylor, K ;
Herrmann, R ;
Lynch, KP ;
Hughes, TP .
BLOOD, 2002, 99 (09) :3472-3475
[6]  
Branford S, 1999, BRIT J HAEMATOL, V107, P587
[7]  
Buchdunger E, 1996, CANCER RES, V56, P100
[8]  
Buchdunger E, 2000, J PHARMACOL EXP THER, V295, P139
[9]   Bcr-Abl inhibition as a modality of CML therapeutics [J].
Buchdunger, E ;
Matter, A ;
Druker, BJ .
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 2001, 1551 (01) :M11-M18
[10]   BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration [J].
Campbell, LJ ;
Patsouris, C ;
Rayeroux, KC ;
Somana, K ;
Januszewicz, EH ;
Szer, J .
CANCER GENETICS AND CYTOGENETICS, 2002, 139 (01) :30-33