Quizartinib [(N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea] is a once-daily, orally administered, potent and
selective inhibitor of FMS-like tyrosine kinase 3
(FLT3) kinase (Kd = 1.6 ± 0.7 nM).
Quizartinib
is a novel compound expressly optimized as a FLT3 inhibitor for the treatment
of Acute Myeloid Leukemia (AML). Quizartinib inhibits FLT3 with low nanomolar
potency in cellular assays and is highly selective when screened against the
majority of the human protein kinome [1, 2].
Quizartinib is currently in development for the treatment of
relapsed or refractory FLT3-ITD positive and negative AML patients and as a
maintenance therapy. Though patients of any age may be FLT3 positive, over 35%
of AML patients over age 55 are estimated to harbour a genetic mutation in
FLT3, known as the FLT3 internal tandem duplication (FLT3-ITD) mutation. The
FLT3-ITD mutation acts like a “power switch” that causes leukemic cells, or
blasts, to spread more aggressively and grow back more rapidly following
chemotherapy, conferring an especially poor survival outcome. Quizartinib is
designed to turn off this switch.
This novel second generation class III receptor tyrosine kinase
inhibitor is currently under clinical investigation for wildtype AML and also
those bearing FLT3 ITD mutation. Quizartinib with superior pharmaceutical
properties and an excellent pharmacokinetic profile is a clear leader as compared
to other agents in clinical trials. A study using recombinant enzyme in in vitro kinase assays identified that Quizartinib
targets related class III RTKs, such as wildtype and gain-of-function mutant
KIT and PDGFR isoforms. This implies that patients with CBF AML with KIT D816Y
or exon 11 mutations or patients with solid tumors associated with KIT and
PDGFR mutations, such as GIST too might benefit from this agent. This would not
include the group of mutant-KIT CBF AML that have KIT D816V mutations [1].
The activity of Quizartinib is as follows:
Kd (FLT3 binding affinity) = 1.6 ± 0.7 nM
Kd (FLT1 binding affinity) = 41 nM
Kd (FLT3(D835H) binding affinity) = 3.7 nM
Kd (FLT3(D835Y) binding affinity) = 7.1 nM
Kd (FLT3(ITD) binding affinity) = 8.8 nM
Kd (FLT3(K663Q) binding affinity) = 2.2 nM
Kd (FLT3(N841I) binding affinity) = 4.1 nM
Kd (FLT4 binding affinity) = 41 nM
Common Name: Quizartinib
Synonyms: AC220; AC 220; AC-220
IUPAC Name: (N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea
CAS Number: 950769-58-1; 1132827-21-4 (dihydrochloride)
SMILES:O=C(NC1=CC=C(C(N=C2SC3=C4)=CN2C3=CC=C4OCCN5CCOCC5)C=C1)NC6=NOC(C(C)(C)C)=C6
Mechanism of Action: Kinase Inhibitor; FLT3 Inhibitor
Indication: Acute Myeloid Leukemia
Development Stage: Phase III
Company: Ambit Biosciences
To assess the potential of Quizartinib to inhibit off-target kinases,
and to compare its selectivity with that of the other FLT3 inhibitors, it was
screened against a KinomeScan panel of 402 kinase binding assays, representing
almost 80% of “typical” human protein kinases. Quizartinib was screened against
the panel at a single concentration of 10 µM in a primary screen, and
dissociation constants (Kds) were determined for all kinases identified as
targets in the primary screen. For Quizartinib, researchers also measured a Kd
for every kinase not found to bind in the primary screen to ensure that no
targets were missed.
The highest affinity target identified for Quizartinib was FLT3.
The only other kinases with binding constants within 10-fold that for FLT3 were
the closely related receptor tyrosine kinases (RTKs) KIT, PDGFRA, PDGFRB, RET,
and CSF1R (Kd = 4.8, 11, 7.7, 9.9 and 12 nM, respectively) and only
4 additional kinases, also related RTKs (FLT1, FLT4, DDR1, VEGFR2 Kd
= 41, 41, 81, 87 nM, respectively), bound with Kds within 100-fold of that for
FLT3. In follow-up cellular assays the activity of Quizartinib against KIT,
RET, CSF1R, and PDGFR was at least 10-fold less potent than the cellular
activity against FLT3, confirming the selectivity observed in the biochemical
assays. The kinase interaction pattern for Quizartinib was therefore highly
focused [1].
To determine the ability of Quizartinib to inhibit FLT3 in the
cellular environment, researchers measured inhibition of FLT3
autophosphorylation in the human leukemia cell lines MV4-11 (IC50 = 0.56
± 0.3 nM), which harbors a homozygous FLT3-ITD mutation and is FLT3 dependent and
RS4;11, which expresses wild-type FLT3. Furthermore, to determine the effect of
FLT3-ITD inhibition on cell growth, researchers measured MV4-11 cell
proliferation in the presence of Quizartinib. The IC50s in this
assay tracked very well with FLT3 autophosphorylation inhibition, with Quizartinib
having values of 4.2 ± 0.3 and 1.1 ± 0.1 for wild type and ITD respectively [1].
References:
1. Zarrinkar, P. P.; et. al. AC220 is a uniquely potent and
selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).
Blood 2009, 114(14), 2984-2992.
2. Bhagwat, S. S.; et. al. Identification of
N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea
dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like
tyrosine kinase-3 (FLT3) inhibitor. J Med Chem 2009, 52(23), 7808-7816.
