CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML).
Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Louise M
LM
Kelly
Jin-Chen
JC
Yu
Christina L
CL
Boulton
Mutiah
M
Apatira
Jason
J
Li
Carol M
CM
Sullivan
Ifor
I
Williams
Sonia M
SM
Amaral
David P
DP
Curley
Nicole
N
Duclos
Donna
D
Neuberg
Robert M
RM
Scarborough
Anjali
A
Pandey
Stanley
S
Hollenbach
Keith
K
Abe
Nathalie A
NA
Lokker
D Gary
DG
Gilliland
Neill A
NA
Giese
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D016026:Bone Marrow Transplantation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007377:Interleukin-3 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D020080:Tandem Repeat Sequences; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D011956:Receptors, Cell Surface; C464670:tandutinib; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D051941:fms-Like Tyrosine Kinase 3