Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Article abstract of DOI:10.1080/14756366.2020.1758689

A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC₅₀= 106 nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC₅₀ value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.

Full text of DOI:10.1080/14756366.2020.1758689

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
Discovery of 5-methyl-N-(2-arylquinazolin-7-
yl)isoxazole-4-carboxamide analogues as highly
selective FLT3 inhibitors
Daseul Im, Hyungwoo Moon, Jinwoong Kim, Youri Oh, Miyoung Jang & Jung-
Mi Hah
To cite this article: Daseul Im, Hyungwoo Moon, Jinwoong Kim, Youri Oh, Miyoung Jang & Jung-
Mi Hah (2020) Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues
as highly selective FLT3 inhibitors, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1,
1110-1115, DOI: 10.1080/14756366.2020.1758689
To link to this article: https://doi.org/10.1080/14756366.2020.1758689
© 2020 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
View supplementary material
Published online: 27 Apr 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=ienz20

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2020, VOL. 35, NO. 1, 1110–1115
https://doi.org/10.1080/14756366.2020.1758689
SHORT COMMUNICATION
Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues
as highly selective FLT3 inhibitors
Daseul Im, Hyungwoo Moon, Jinwoong Kim, Youri Oh, Miyoung Jang and Jung-Mi Hah
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Korea
ABSTRACT
ARTICLE HISTORY
Received 26 December 2019
Revised 2 April 2020
Accepted 10 April 2020
A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised
based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues
displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-
(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activ-
ity against FLT3 (IC50¼ 106nM) with excellent selectivity profiles over 36 other protein kinases including
cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC50 value of 301nM, and other
FLT3 mutants showing potential as an AML therapeutics.
KEYWORDS
FLT3; FLT3-ITD; FLT3-TKD;
quinazoline; selectivity
1. Introduction
Introducing quinazoline into type II FMS kinase inhibitor, we could
discover a novel FLT3 inhibitor with excellent selective profile.
FLT3,
a type of trans-membrane receptor tyrosine kinase
expressed on lympho-hematopoietic cells, is an attractive target in
acute myeloid leukaemia (AML)1. When FLT3 ligand binds to FLT3
kinase, it is activated by auto-phosphorylation, which then acti-
vates its multiple downstream signalling pathways, including sig-
nal transducer and activator of transcription 5 (STAT5), ras/
mitogen-activated protein kinase, and phosphatidylinositol 3-kin-
ase/Akt pathways, playing a key role in cell proliferation, survival,
2. Results and discussion
Scheme 1 shows the general synthetic route for quinazolinyl-iso-
xazole-4-carboxamide analogues (7a–q). First, 2-amino-4-nitro-ben-
zoic acid (1) was converted to 2-amino-4-nitrobenzamide (2) and
then reduced to 2-(aminomethyl)-5-nitroaniline (3) using borane-
tetrahydrofuran. Then, the benzyl amine was coupled with various
benzoyl chlorides to produce carboxamide derivatives (4a–q); sub-
sequently, benzamide was treated with concentrated HCl in acetic
and subjected to microwave irradiation at 150 ꢀC for cyclisation to
yield a dihydroquinazoline compound. Without further purifica-
tion, they were treated with p-chloranil oxidising agent to obtain
quinazoline derivatives (5a–q) as core intermediates. Next, the
nitro group was reduced to amine (6a–q) using Fe catalyst and
was then coupled with isoxazole chloride to produce the final qui-
nazolinyl-isoxazole-4-carboxamides (7a–q).
and immune response2–5
.
However, mutation of FLT3 causes its ligand-independent acti-
vation and can be classified by location and type, including
internal tandem duplication (ITD) and point mutation in the tyro-
sine kinase domain (TKD). FLT3-ITD mutations are present in
20–30% of AML patients and are especially related to leucocytosis
and poor prognosis and point mutation in TKD is found in 5% of
AML patients6. Despite the significance of seeking AML therapeu-
tics, only a few molecules have been approved, such as midos-
taurin and gilteritinib (ASP2215), which are depicted in Figure 17,8
.
All quinazoline compounds, 7a–q, were evaluated for their
activity against FLT3 kinase and FLT3-ITD mutation and the results
are shown in Table 1. Most of the synthesised compounds exhib-
ited selective activity against FLT3, particularly those incorporating
the piperazine moiety. Among the compounds evaluated, 7d
showed the most potent activity against FLT3 with an IC50 value
of 106 nM, and FLT3-ITD with an IC50 value of 301 nM. Structure
activity relationships (SARs) were inferred from the data.
Protein kinase inhibitors can be classified as type I, II, III, IV and
V9 based on their binding mode. Among these inhibitors, type II
kinase inhibitor can take advantage of selectivity acquisition and
exhibits promising potency due to additional interaction with the
DFG pocket adjacent to the ATP-binding pocket on top of the
hinge hydrogen bond in the ATP site10. Previously, we reported
very potent type II FMS inhibitors11 and selective benzimidazole-
incorporated FLT3 inhibitors12. Here, we demonstrate that the
amide or urea between the middle phenyl ring and the secondary
hydrophobic aromatic ring can be rigidified further, introducing a
quinazoline structure as a bioisostere (Figure 2). The quinazoline
structures are well-known privileged structures in medicinal chem-
In our previous work, benzimidazole compounds retained their
activity against FLT3 regardless of presence of 1,3,5-substituted or
1,3,4-substituted benzoic acid, and the activity was determined as
piperazine > imidazole > morpholine substituents12. We optimised
istry, exhibiting diverse biological activities13. However, this is the quinazoline derivatives based on the observation of previous
first attempt to incorporate one in type II PKI modification. benzimidazole derivatives. Those with methyl piperazine or
CONTACT Jung-Mi Hah
jhah@hanyang.ac.kr
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55
Hanyandaehak-ro Sangnok-gu, Ansan, Gyeonggi-do, 15588, Korea
Supplemental data for this article can be accessed here.
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1111
morpholine as the phenyl substitution group (7d and 7b) were exhibited decreased activity, about 10-fold less than that of 7d.
more potent about 2- to 5-fold (IC50 values of 0.106 and 3.98 mM, On the predicted binding mode of 7d, strong ionic interaction
respectively) compared to corresponding benzimidazole series between the protonated nitrogen of the piperazine and Asp829
(IC50 values of 0.495 and 7.94 mM), and 7c displayed better might enhance its binding affinity. Almost the same ionic inter-
potency (IC50 value of 1.58 mM) than that of benzimidazole (IC50 action seems possible in case 7e, but the ionic interaction might
value of 2.33 mM). Introduction of 3,5-disubstituted benzoic acid
through quinazoline connection maintained the activity (7b, 7c,
7d, 7e, 7n), but quinazoline compound with 1,3,4-substituted
benzoic acid (7a) and one with pyrazole (7h) caused loss of activ-
ity towards FLT3.
With the result of 7d, we synthesised compound 7e to opti-
mise the linkage between the phenyl group and the piperazine
moiety. Although inhibitory activity towards FLT3 was retained, 7e
push the whole compound slightly out of the active site due to
its length, resulting in loss of multiple interactions such as hydro-
gen bonding with Asp829, p–p interaction with Phe691, and
p–cation interaction with Lys644 (Figure 3). We also replaced
piperazine with a piperidine moiety (7n) to investigate the role of
nitrogen in the piperazine structure. The IC50 value of 7n was
3.59 mM, similar but weaker than 7e despite their similar struc-
tures. Our docking study showed that one conformer of 7n with
equatorial O linkage bound with FLT3 similarly to compound 7e,
but the other conformer with axial O linkage was not suitable to
bind tightly to the active site because of its non-linear piperidine
moiety (Figure 4).
We diversified our quinazoline compounds for further optimisa-
tion, introducing a halogen group (7f, 7g, and 7i), tert-butyl isoxa-
zole (7l), and styrenyl group (7j and 7k). However, only 7j
exhibited competitive activity against FLT3, with an IC50 value of
4.7 mM. In addition, we tried to introduce isoxazole, indazole, ace-
tyl piperidine, and pyridine (7l–q). Compound 7m showed activity
against FLT3, with an IC50 value of 0.79 mM. Compounds 7l, 7o,
7p, and 7q did not show inhibitory activity towards FLT3 or were
very weak. The tert-butyl isoxazole, acetyl piperidine, and pyridine
moieties were less basic than other moieties (piperazine, morpho-
line, imidazole, indazole, and piperidine). For inhibition against
Figure 1. FLT3 inhibitors approved by the FDA as AML treatment.
Figure 2. Design of quinazoline derivatives as bioisosteres of the middle phenyl ring-amide-bond.
Scheme 1. Syntheses of 1H-quinazolyl isoxazole-4-carboxamide derivatives. (i) EDC, HOBt, TEA, NH3 in MeOH, rt; (ii) BH3-THF, reflux; (iii) benzoyl chloride, CH2Cl2, 0
oC! rt; (iv) (1) HCl/H2O/AcOH, lW, 150 oC, 10min; (2) p-chloranil, toluene, reflux; (v) Fe, AcOH/H2O/EtOH, 60 oC; (vi) 5-methylisoxazole-4-carbonyl chloride, TEA,
THF, rt.

1112
D. IM ET AL.
Table 1. Enzymatic activity of 5-methyl-N-(2-arylquinazolin-7-yl) isoxazole-4-carboxamide analogues.
FLT
FLT
FLT3
FLT3
(ITD)
(ITD)
No.
7a
R
No.
7j
R
IC50 (µM)
IC50 (µM)
NA
NA
4.70
NA
5.00
NA
7b
7c
7d
3.98
3.11
7k
7l
1.58
3.16
NA
NA
7m
7n
7o
0.79
3.59
NA
0.908
4.96
NA
0.106
1.03
0.301
13.9
7e
7f
NA
NA
NA
NA
7g
7p
7q
>10
NA
>10
NA
7h
7i
NA
NA
NA
NA
1.13
nM
0.88
nM
Staurosporine
FLT3, the ionic interaction with Asp829 seems to play a crucial. conformation of kinase and type II inhibitors generally could not
Compounds incorporating basic moieties (7b, 7c, 7d, 7e, 7j, 7m, bind well enough. This is also known to be a mechanism of sec-
and 7n) maintained inhibitory activity towards FLT3, while com- ondary resistance of type II FLT3 inhibitor.13 Nevertheless, our
pounds that were substituted with less basic moieties (7o, 7p, compound 7d, which is a type II FLT3 inhibitor, exhibits a potent
and 7q) lost the activity. The quinazoline derivatives were also inhibitory activity (IC50 ¼ 228 nM) in FLT3-TKD (D835Y) similar to
tested for their activity against FLT3-ITD, and they displayed that of FLT3 wild type also. FLT3-TKD, especially D835Y, D835H
inhibitory activity against FLT3-ITD similar to level of activity on mutant was identified as a main drug resistance mechanism of
FLT3 (7b, 7c, 7d, 7j, 7m, and 7n).
FLT3 inhibitor in the clinical trial.15–18 Like quizartinib, 7d displays
Moreover, the most potent 7d was examined further for inhibi- potent inhibitory activity against FLT3-TKD (D835Y) with value of
tory activity against other FLT3 mutants and the result was IC50 228 nM, while decreased about 2-fold compared to that of
impressive (Table 2). The 7d was a potent inhibitor towards FLT3 FLT3 wild type.
(F594_R_R595) (IC50 ¼ 0.524 mM), FLT3 (F594_EY_R595) (IC50
Next, we investigated kinase panel screening of 7d and 7b
¼
0.495 mM), FLT3 (Y591_ VDFREYEYD_V592) (IC50 ¼ 0.728 mM), and over 36 different kinases at a single dose of 10 mM (Figure 5). Both
FLT3 (D835Y), with an IC50 value of 0.228 mM. Since FLT3-ITD compounds 7d and 7b (data in Supplementary material) showed
mutation occur mainly in the juxtamembrane domain away from an excellent selectivity profile, having almost no activity on other
the ATP binding site, the FLT3 inhibitors binding in ATP site kinases including FMS and cKit. High selectivity over cKit might be
exhibit potency against FLT3-ITD mutant14. On the other hand, a an opportunity to avoid myelosuppression toxicity, which was
mutation in active site such as FLT3 (D835Y) induces active reported from a dual FLT3/cKit inhibitor19–22. It is a valuable result

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1113
Figure 3. (Left) Compound 7d (green) at the active site of FLT3 (PDB: 4RT7); (right) 7e (yellow) at the active site of FLT3 (PDB: 4RT7).
Figure 4. (Left) Compound 7n with equatorial O linkage (orange) at the active site of FLT3 (PDB: 4RT7); (right) compound 7n with axial O linkage (azure) at the active
site of FLT3 (PDB: 4RT7).
Table 2. Enzymatic activities of compound 7d
against FLT3 mutants.
of multiple interactions: one hydrogen bond with Asp829, p–p
interaction with Phe691, and p-cation interaction with Lys644. As
it was designed as a hybrid of the middle phenyl ring and urea
(or amide) linker, the quinazoline seems tightly bound with ATP-
binding site and adjacent region like other type II inhibitors.
However, instead of fitting into a hydrophobic pocket surrounded
by hydrophobic residue, the strong ionic interaction between the
protonated nitrogen of the piperazine ring and the Asp796 might
enhance the binding affinity, resulting in potent inhibitory activity
and considerable selectivity about FLT3. Due to its strong ionic
interaction, the fused ring system of quinazoline might make add-
itional interactions in the active site of FLT3 unlike benzimidazole
derivative12. The quinazoline derivative 7d interacts with not only
Lys644 (p–cation interaction between guanidine group of Lys644
and quinazoline ring) also gatekeeper residue, Phe691, (p–p inter-
Kinase
IC50 (mM)
FLT3 (F594_R595 ins R)
FLT3 (F594_R595 ins EY)
FLT3 (Y591_V592 ins VDFREYEYD)
FLT3 (D835Y)
0.524
0.495
0.728
0.228
to secure such a kinase selectivity profile considering the similar-
ities of the same type III receptor tyrosine kinase (FMS, cKit
and FLT3).
For better understanding of the interactions between our com-
pounds and FLT3, molecular docking of compound 7d into the
ATP binding pocket of FLT3 (PDB: 4RT7) was performed using action between phenyl group of side chain and quinazoline struc-
€
Glide software (Schrodinger, Version 14.2). The docking result is ture) properly, which could contribute to enhanced activity
depicted in Figure 6. In the binding model of 7d, 5-methyisoxa- of compound 7d presumably compared with benzimida-
zole compound12.
zole forms a p-p interaction with Phe830 instead of hydrogen
bonding with Cys694, contrast to the co-crystal structure of quir-
We also tried to explain the selectivity of quinazoline com-
zatinib23. Instead, the quinazoline ring of 7d showed possibilities pound for FMS and cKit. As shown in Figure 6, FMS kinase has

1114
D. IM ET AL.
Figure 5. Kinase profiling according to chemical scaffold. The profiles of the FMS kinase inhibitor [13] and quinazoline derivative 7d (10lM) are shown.
Figure 6. (left) Docking structures of 7d in FLT3 (PDB: 4RT7) and 7d in FMS (PDB:3LCO).
Thr663 instead of Phe691 in the active site. 7d could not bind does not form any interaction with Thr663 or other residue. The
well in the FMS kinase without multiple interaction which quina- difference of only one residue in the highly conserved active site
zoline forms. Although 7d forms hydrogen bonding with Cys666 seems to play crucial role in selectivity profile and the interaction
and strong ionic interaction with Asp796, the quinazoline moiety between quinazoline structure and Phe691 also seems to be

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1115
important to binding affinity. In the case of cKit kinase, threonine
residue locates at the same position, and same explanation could
be applied.
FLT3 mutated acute myeloid leukemia. Invest New Drugs
2017;35:556–65.
8. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of
FLT3 by gilteritinib in relapsed or refractory acute myeloid
leukaemia: a multicentre, first-in-human, open-label, phase
1–2 study. Lancet Oncol 2017;18:1061–75.
3. Conclusions
9. Wu P, Nielsen TE, Clausen MH. FDA-approved small-mol-
ecule kinase inhibitors. Trends Pharmacol. Sci 2015;36:
422–39.
10. Versele M, Haefner B, Wroblowski B, et al. Covalent Flt3-
Cys828 inhibition represents a novel therapeutic approach
for the treatment of Flt3- ITD and Flt3-D835 mutant acute
myeloid leukemia. Cancer Res 2016;76:4800.
11. Im D, Jung K, Yang S, et al. Discovery of 4-arylamido 3-
methyl isoxazole derivatives as novel FMS kinase inhibitors.
Eur J Med Chem 2015;102:600–10.
12. Im D, Moon H, Kim J, et al. Conformational restriction of a
type II FMS inhibitor leading to discovery of 5-methyl- N-(2-
aryl-1H-benzo[d]imidazo-5-yl)isoxazole-4-carboxamide ana-
logues as selective FLT3 inhibitors. J Enzyme Inhib Med
Chem 2019;34:1716–21.
13. Kamal A, Reddy K, Devaiah V, et al. Recent advances in the
solid-phase combinatorial synthetic strategies for the qui-
noxaline, quinazoline and benzimidazole based privileged
structures. Mini-Rev Med Chem 2006;6:71–89.
14. Chen Y, Pan Y, Guo Y, et al. Tyrosine kinase inhibitors target-
ing FLT3 in the treatment of acute myeloid leukemia. Stem
Cell Investig 2017;4:48–13.
We designed and synthesised a series of 4-arylamido 5-methyli-
soxazole derivatives containing quinazoline using a conformational
rigidification strategy. Various analogues were synthesised and
tested for inhibitory activity against FLT3. Compound 7d displayed
the most potent inhibitory activity against FLT3, with an IC50 of
106 nM, and was also active against FLT3-ITD and FLT3-TKD
(D835Y), with an IC50 of 301 nM and 228 nM respectively. The
novel type II FLT3 inhibitors showed an excellent selectivity profile
having 20% or less activity towards other kinases including similar
FMS, cKit. Specifically, the selectivity over FMS and cKit potentially
relieve the myelosuppression toxicity observed in the dual FLT3/
cKit kinase inhibitor. Molecular docking of 7d into the ATP bind-
ing site of FLT3 kinase was performed and the result disclosed
that the quinazoline structure could perform an adequate or even
better bioisostere of benzimidazole in previous report.
Considering that FLT3 and FLT3 mutants have been significantly
associated with FLT3 mutant-mediated AML, compound 7d could
be a valuable molecule for FLT3-mutant positive physiology and
pathology research and a potential therapeutic agent. Even if fur-
ther optimisation would be necessary in terms of potency, our
research towards a novel selective FLT3 inhibitor suggests the
potential of quinazoline compounds as AML therapeutics.
15. Smith CC, Lin K, Stecula A, et al. FLT3 D835 mutations con-
fer differential resistance to type II FLT3 inhibitors. Leukemia
2015;29:2390–2.
16. Levis M. FLT3 mutations in acute myeloid leukemia?: What
is the best approach in 2013? Hematology Am Soc Hematol
Educ Program 2013;2013:220–6.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
17. Sun D, Yang Y, Lyu J, et al. Discovery and rational design of
pteridin-7(8H)-one-based inhibitors targeting FMS-like tyro-
sine kinase 3 (FLT3) and its mutants. J Med Chem 2016;59:
6187–200.
This work was financially supported by grants from the National
Research Foundation of Korea [NRF-2017R1A2B4006447 and NRF-
2019M3A9A8066500; J.-M. Hah].
18. Roskoski R. Properties of FDA-approved small molecule pro-
tein kinase inhibitors. Pharmacol Res 2019;144:19–50.
19. Fathi AT, Chen YB. The role of FLT3 inhibitors in the treat-
References
ment of FLT3-mutated acute myeloid leukemia. Eur
J
1. Swords R, Freeman C, Giles F. Targeting the FMS-like tyro-
sine kinase 3 in acute myeloid leukemia. Leukemia 2012;26:
2176–85.
Haematol 2017;98:330–6.
20. Chen Y, Pan Y, Guo Y, et al. Tyrosine kinase inhibitors target-
ing FLT3 in the treatment of acute myeloid leukemia. Stem
Cell Invest 2017;4:48–52.
2. Drexler HG. Expression of FLT3 receptor and response to
FLT3 ligand by leukemic cells. Leukemia 1996;10:588–99.
3. Zhang S, Fukuda S, Lee Y, et al. essential role of signal trans-
ducer and activator of transcription (Stat)5a but not Stat5b
for Flt3-dependent signaling. J Exp Med 2000;192:719–28.
4. Takahashi S. Downstream molecular pathways of FLT3 in the
pathogenesis of acute myeloid leukemia: Biology and thera-
peutic implications. J Hematol Oncol 2011;1:1–10.
5. Gary Gilliland D, Griffin JD. The roles of FLT3 in hematopoi-
esis and leukemia. Blood 2002;100:1532–42.
6. Larrosa-Garcia M, Baer MR. FLT3 inhibitors in acute myeloid
leukemia: current status and future directions. Mol Cancer
Ther 2017;16:991–1001.
21. Warkentin AA, Lopez MS, Lasater EA, et al. Overcoming mye-
losuppression due to synthetic lethal toxicity for FLT3-tar-
geted acute myeloid leukemia therapy. Elife 2014;3:e03445.
22. Liang X, Wang B, Chen C, et al. Discovery of N-(4-(6-acetami-
dopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)ace-
tamide (CHMFL-FLT3-335) as a potent Fms-like tyrosine
kinase 3 internal tandem duplications (FLT3-ITD) mutant
selective inhibitor for acute myeloid leukemia. J Med Chem
2019;62:875–892.
23. Smith CC, Lin KC, Zhang Y, et al. Characterizing and overrid-
ing the structural mechanism of the quizartinib-resistant
FLT3 “gatekeeper” F691L mutation with PLX3397. Cancer
Discov 2015;5:668–79.
7. Mori M, Kaneko N, Ueno Y, et al. Gilteritinib, a FLT3/AXL
inhibitor, shows antileukemic activity in mouse models of