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Table 1.

Selection of agents with activity against BCR-ABL1 T315I-positive cells

CompoundChemical classAurora selectivityOther targetsRouteStageCommentsClinical trial in CML
MK-0457 Pyrazolo-quinazoline Pan-Aurora ABL1, JAK2, FLT3 i.v. Phase II Also being tested in patients with JAK2 V617F+ MPDs NCT00405054 
PHA-739358 Pyrrolo-pyrazole Pan-Aurora ABL1, RET, TRK-A, FGFR1 i.v. Phase II Being tested in CML after failure of imatinib or other antiABL therapy NCT00335868 
XL228 Not disclosed Aurora A ABL1, IGF1R, SRC i.v. Phase I Being tested in CML and Ph+ALL after failure of imatinib or dasatinib therapy NCT00464113 
KW-2449 Not disclosed Aurora A FGFR1, FLT3, VEGFR Oral Phase I Being tested in acute leukemia, high-risk MDS, and CML NCT00346632 
AT-9283 Not disclosed Pan-Aurora ABL1, JAK2, JAK3, FLT3 i.v./Oral Phase I/II Being tested in patients with refractory hematologic malignancies NCT00522990 
VE-465 Pyrazolo-quinazoline Pan-Aurora Not disclosed NA Preclinical Structurally related to MK-0457 NA 
DCC-2036 Not disclosed None ABL1, FLT3, SRC NA Preclinical Target switch pocket. Non-ATP competitive ABL1 inhibitor. High ABL1 kinase residency time NA 
17AAG Benzoquinone None HSP90, ABL1, MEK, AKT i.v. Phase I Inhibitor of HSP90. Depletes BCR-ABL1 via proteasome-mediated degradation NCT00100997 
FTY720 Myriocin derivative None PP2A, sphingosine-1-phosphate receptors Oral Preclinical Novel immunosuppressant. Active in multiple sclerosis NA 
HHT Cephalotaxine None MCL-1 s.c./i.v. Phase II/III Synergistic with the NCT00375219 
 ester     BH3 mimetic ABT-737 NCT00462943 
       NCT00114959 
LBH589 Hydroxamic acid None HDAC-6, HSP90 Oral Phase II/III Synergistic with NCT00451035 
 derivative     nilotinib NCT00449761 
CompoundChemical classAurora selectivityOther targetsRouteStageCommentsClinical trial in CML
MK-0457 Pyrazolo-quinazoline Pan-Aurora ABL1, JAK2, FLT3 i.v. Phase II Also being tested in patients with JAK2 V617F+ MPDs NCT00405054 
PHA-739358 Pyrrolo-pyrazole Pan-Aurora ABL1, RET, TRK-A, FGFR1 i.v. Phase II Being tested in CML after failure of imatinib or other antiABL therapy NCT00335868 
XL228 Not disclosed Aurora A ABL1, IGF1R, SRC i.v. Phase I Being tested in CML and Ph+ALL after failure of imatinib or dasatinib therapy NCT00464113 
KW-2449 Not disclosed Aurora A FGFR1, FLT3, VEGFR Oral Phase I Being tested in acute leukemia, high-risk MDS, and CML NCT00346632 
AT-9283 Not disclosed Pan-Aurora ABL1, JAK2, JAK3, FLT3 i.v./Oral Phase I/II Being tested in patients with refractory hematologic malignancies NCT00522990 
VE-465 Pyrazolo-quinazoline Pan-Aurora Not disclosed NA Preclinical Structurally related to MK-0457 NA 
DCC-2036 Not disclosed None ABL1, FLT3, SRC NA Preclinical Target switch pocket. Non-ATP competitive ABL1 inhibitor. High ABL1 kinase residency time NA 
17AAG Benzoquinone None HSP90, ABL1, MEK, AKT i.v. Phase I Inhibitor of HSP90. Depletes BCR-ABL1 via proteasome-mediated degradation NCT00100997 
FTY720 Myriocin derivative None PP2A, sphingosine-1-phosphate receptors Oral Preclinical Novel immunosuppressant. Active in multiple sclerosis NA 
HHT Cephalotaxine None MCL-1 s.c./i.v. Phase II/III Synergistic with the NCT00375219 
 ester     BH3 mimetic ABT-737 NCT00462943 
       NCT00114959 
LBH589 Hydroxamic acid None HDAC-6, HSP90 Oral Phase II/III Synergistic with NCT00451035 
 derivative     nilotinib NCT00449761 

Abbreviations: FLT3, Fms-like tyrosine kinase 3; IGF1R, insulin-like growth factor type-1 receptor; FGFR1, fibroblast growth factor receptor-1; MPD, myeloproliferative disorder; Ph+, Philadelphia chromosome positive; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; HSP90, heat shock protein 90; HDAC-6, histone deacetylase 6; HHT, homoharringtonine; NA, not applicable.

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