KW-2449 [(E)-(4-(2-(1H-indazol-3-yl)vinyl)phenyl)(piperazin-1-yl)methanone]
is an orally available multikinase inhibitor of FMS-like receptor tyrosine kinase (FLT3), ABL, ABL-T315I, and
Aurora kinase. It is currently in Phase I trials for leukemia patients. KW-2449
inhibited FLT3 and ABL kinases with half-maximal inhibitory concentration (IC50)
values of 0.0066 and 0.014 µM, respectively. In addition, it potently inhibited
ABL-T315I, which is associated with IM resistance, with an IC50
value of 0.004 µM. On the other hand, KW-2449 had little effect on PDGFRβ, IGF-1R, EGFR, and various
serine/threonine kinases even at a concentration of 1 µM. Among various
serine/threonine kinases examined, KW-2449 inhibited Aurora A kinase with IC50
of 0.048 µM and Aurora B kinase with the equivalent potency.
The researchers at Kyowa Hakko Kirin (previously Kyowa Hakko
Kogyo) aimed at designing an orally available and highly potent FLT3 inhibitor
with low toxicity profile for leukemia patients. For this goal, they screened
the in-house chemical libraries using several leukemia cells, which have
several activated mutations in FLT3 or BCR-ABL translocation. As a result, they
identified several chemo-types with different kinase inhibition profiles,
intensively studied the structures of the identified chemo-types to improve the
potency and selectivity, and then finally generated KW-2449 [1].
Preclinical studies revealed that
KW-2449 is converted by monoamine oxidase-B (MAO-B) and aldehyde oxidase into
its major metabolite M1. Metabolite M1 is 3.6-fold less potent than the parent
drug. The combination of KW-2449 and metabolite can successfully inhibit FLT3
in patients, and FLT3 mutant patients treated with KW-2449 on a twice daily
schedule display the typical, short-lived reduction in peripheral blasts that
has been seen with the other FLT3 inhibitors in development.
The activity of KW-2449 is as follows:
IC50 (FLT3 enzyme
assay) = 0.0066 uM
IC50 (FLT3-D835Y
enzyme assay) = 0.001 uM
IC50 (KIT enzyme
assay) = 0.3 uM
IC50 (PDFGRα enzyme assay) = 1.7 uM
IC50 (ABL enzyme
assay) = 0.014 uM
IC50 (ABL-T315I
enzyme assay) = 0.004 uM
IC50 (SRC enzyme
assay) = 0.4 uM
IC50 (JAK2 enzyme
assay) = 0.15 uM
IC50 (FGFR1 enzyme
assay) = 0.036 uM
IC50 (AURKA enzyme
assay) = 0.048 uM
Common Name: KW-2449
Synonyms: KW2449; KW-2449; KW 2449
IUPAC Name: (E)-(4-(2-(1H-indazol-3-yl)vinyl)phenyl)(piperazin-1-yl)methanone
CAS Number: 1000669-72-6
Mechanism of Action: Kinase Inhibitor; FLT3 Inhibitor; ABL Inhibitor; Aurora
Kinase Inhibitor; MultiKinase Inhibitor
Indication: Various Cancers; Leukemia
Development Stage: Phase I
Company: Kyowa Hakko Kirin Pharmaceuticals
FMS-like receptor tyrosine kinase (FLT3) is a class III receptor tyrosine kinase together with cKIT, FMS, and PDGFR. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence; subsequently, a missense point mutation at the Asp835 residue and point mutations, deletions, and insertions in the codons surrounding Asp835 within a tyrosine kinase domain of FLT3 (FLT3/KDM) have been found. FLT3 mutation is the most frequent genetic alteration in acute myeloid leukemia (AML) and involved in the signaling pathway of proliferation and survival in leukemia cells. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. In addition to FLT3 mutation, overexpression of FLT3 is an unfavorable prognostic factor for overall survival in AML, and it has been revealed that overexpressed FLT3 had the same sensitivity to the FLT3 inhibitor as FLT3/ITD [1]. Acute leukemia is a complex multigenetic disorder, a simultaneous inhibition of multiple protein kinases is thought to be advantageous over the increasing potency against the selective kinases.
In vitro kinase inhibition profile of KW-2449 indicated its extreme potency against FLT3 kinase. KW-2449 showed growth inhibitory activities against FLT3/ITD-, FLT3/D835Y-, and wt-FLT3/FL-expressing 32D cells, MOLM-13 and MV4;11 with half-maximal growth inhibitory concentration (GI50) values of 0.024, 0.046, 0.014, 0.024, and 0.011 µM, respectively [1].
FMS-like receptor tyrosine kinase (FLT3) is a class III receptor tyrosine kinase together with cKIT, FMS, and PDGFR. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence; subsequently, a missense point mutation at the Asp835 residue and point mutations, deletions, and insertions in the codons surrounding Asp835 within a tyrosine kinase domain of FLT3 (FLT3/KDM) have been found. FLT3 mutation is the most frequent genetic alteration in acute myeloid leukemia (AML) and involved in the signaling pathway of proliferation and survival in leukemia cells. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. In addition to FLT3 mutation, overexpression of FLT3 is an unfavorable prognostic factor for overall survival in AML, and it has been revealed that overexpressed FLT3 had the same sensitivity to the FLT3 inhibitor as FLT3/ITD [1]. Acute leukemia is a complex multigenetic disorder, a simultaneous inhibition of multiple protein kinases is thought to be advantageous over the increasing potency against the selective kinases.
In vitro kinase inhibition profile of KW-2449 indicated its extreme potency against FLT3 kinase. KW-2449 showed growth inhibitory activities against FLT3/ITD-, FLT3/D835Y-, and wt-FLT3/FL-expressing 32D cells, MOLM-13 and MV4;11 with half-maximal growth inhibitory concentration (GI50) values of 0.024, 0.046, 0.014, 0.024, and 0.011 µM, respectively [1].
References:
1. Shiotsu, Y.; et. al. KW-2449, a novel multikinase inhibitor, suppresses the
growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL
translocation. Blood 2009, 114(8), 1607-1617.
2. ClinicalTrials.gov Safety, Tolerability, and
Pharmacokinetic/Pharmacodynamic Study of KW-2449 in Acute Myelogenous Leukemia
(AML) (Protocol Number: 2449-US-002). NCT00779480. Retrieved (01-09-2015)
3. ClinicalTrials.gov An Ascending Dose Study of
KW-2449 in Acute Leukemias, Myelodysplastic Syndromes, and Chronic Myelogenous
Leukemia. NCT00346632. Retrieved (01-09-2015)
