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.
Zhang
Jianming
J
Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.
Adrián
Francisco J
FJ
Jahnke
Wolfgang
W
Cowan-Jacob
Sandra W
SW
Li
Allen G
AG
Iacob
Roxana E
RE
Sim
Taebo
T
Powers
John
J
Dierks
Christine
C
Sun
Fangxian
F
Guo
Gui-Rong
GR
Ding
Qiang
Q
Okram
Barun
B
Choi
Yongmun
Y
Wojciechowski
Amy
A
Deng
Xianming
X
Liu
Guoxun
G
Fendrich
Gabriele
G
Strauss
André
A
Vajpai
Navratna
N
Grzesiek
Stephan
S
Tuntland
Tove
T
Liu
Yi
Y
Bursulaya
Badry
B
Azam
Mohammad
M
Manley
Paul W
PW
Engen
John R
JR
Daley
George Q
GQ
Warmuth
Markus
M
Gray
Nathanael S
NS
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D003460:Crystallization; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001549:Benzamides; C508526:GNF-2 compound; D010879:Piperazines; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib