VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.
In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.
University of Kentucky, Department of Chemistry, Lexington Kentucky 40506, United States.
David K
DK
Heidary
George
G
Huang
Diane
D
Boucher
Jianguo
J
Ma
Cornelia
C
Forster
Ron
R
Grey
Jinwang
J
Xu
Michael
M
Arnost
Deborah
D
Choquette
Guanjing
G
Chen
Jie-Hua
JH
Zhou
Yung-Mae
YM
Yao
Edward D
ED
Ball
Mark
M
Namchuk
Robert J
RJ
Davies
Greg
G
Henkel
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D044967:Serum; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D009025:Morpholines; C568953:N3-(4-(4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine; D014230:Triazoles; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3