Description
KW-2449 is a potent multikinase inhibitor (IC50’s: FLT3 = 7 nM, FGFR1 = 36 nM, Abl = 14 nM, Abl-T315 = 4 nM) with anti-leukemic effects.1,2,3
Uses
KW-2449 is a multi-targeted kinase inhibitor of FLT3, ABL, ABLT315I and Aurora kinase with IC50s of 6.6, 14, 4 and 48 nM, respectively.
Definition
ChEBI: [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone is a member of indazoles.
in vivo
Oral administration of KW-2449 shows dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induces the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributes to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 is confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as α1-acid glycoprotein[1].
IC 50
Abl: 4 nM (IC
50); ABL-T315I: 14 nM (IC
50); FGFR1: 36 nM (IC
50); Aurora A: 48 nM (IC
50); FLT3/D835Y: 1 nM (IC
50); FLT3: 6.6 nM (IC
50); JAK2: 150 nM (IC
50); SRC: 400 nM (IC
50); PDFGRα: 1700 nM (IC
50)
References
Shiotsu et al. (2007) KW-2449, a Novel Multi-Kinase Inhibitor Against FLT3, Abl, FGFR1, and Aurora, Suppresses the Growth of AML Both In Vitro and In Vivo; Blood; 110 1832
Shiotsu et al. (2009) KW-2449, a Novel Multi-Kinase Inhibitor, suppresses the growth of leukemia cells with FLTY3 mutations or T315l-mutated BCR/ABL translocation; Blood; 114 1607
Pratz et al. (2009) A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response; Blood; 113 3938
![[4-[2-(1H-Indazol-3-yl)ethenyl]phenyl]-1-piperazinylmethanone Structure](https://www.chemicalbook.com/CAS/GIF/1000669-72-6.gif)
