Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGJCWZ)

• DTT Name: Fms-like tyrosine kinase 3 (FLT-3)
• Synonyms: Stem cell tyrosine kinase 1; STK1; STK-1; Receptor-type tyrosine-protein kinase FLT3; Fetal liver kinase-2; FLT-3; FLK2; FLK-2; FL cytokine receptor; CD135
• Gene Name: FLT3
• DTT Type: Successful target; [1]
• Related Disease:
  Acute myeloid leukaemia [ICD-11: 2A60]
  Bone/articular cartilage neoplasm [ICD-11: 2F7B]
  Colorectal cancer [ICD-11: 2B91]
  Human immunodeficiency virus disease [ICD-11: 1C60-1C62]
  Idiopathic interstitial pneumonitis [ICD-11: CB03]
  Mastocytosis [ICD-11: 2A21]
  Mature B-cell lymphoma [ICD-11: 2A85]
• BioChemical Class: Kinase
• UniProt ID: FLT3_HUMAN
• TTD ID: T74312
• EC Number: EC 2.7.10.1
• Sequence:
  MPALARDGGQLPLLVVFSAMIFGTITNQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESP
  EDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDL
  QNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQD
  ALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRE
  CTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEM
  STYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYE
  IDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHA
  ENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITE
  GVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQD
  NISFYATIGVCLLFIVVLTLLICHKYKKQFRYESQLQMVQVTGSSDNEYFYVDFREYEYD
  LKWEFPRENLEFGKVLGSGAFGKVMNATAYGISKTGVSIQVAVKMLKEKADSSEREALMS
  ELKMMTQLGSHENIVNLLGACTLSGPIYLIFEYCCYGDLLNYLRSKREKFHRTWTEIFKE
  HNFSFYPTFQSHPNSSMPGSREVQIHPDSDQISGLHGNSFHSEDEIEYENQKRLEEEEDL
  NVLTFEDLLCFAYQVAKGMEFLEFKSCVHRDLAARNVLVTHGKVVKICDFGLARDIMSDS
  NYVVRGNARLPVKWMAPESLFEGIYTIKSDVWSYGILLWEIFSLGVNPYPGIPVDANFYK
  LIQNGFKMDQPFYATEEIYIIMQSCWAFDSRKRPSFPNLTSFLGCQLADAEEAMYQNVDG
  RVSECPHTYQNRRPFSREMDLGLLSPQAQVEDS
• Function: Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Hematopoietic cell lineage (hsa04640)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  FLT3 Signaling (R-HSA-9607240)
  STAT5 Activation (R-HSA-9645135)
  FLT3 mutants bind TKIs (R-HSA-9702509)
  STAT5 activation downstream of FLT3 ITD mutants (R-HSA-9702518)
  KW2449-resistant FLT3 mutants (R-HSA-9702569)
  semaxanib-resistant FLT3 mutants (R-HSA-9702577)
  crenolanib-resistant FLT3 mutants (R-HSA-9702581)
  gilteritinib-resistant FLT3 mutants (R-HSA-9702590)
  lestaurtinib-resistant FLT3 mutants (R-HSA-9702596)
  midostaurin-resistant FLT3 mutants (R-HSA-9702600)
  pexidartinib-resistant FLT3 mutants (R-HSA-9702605)
  ponatinib-resistant FLT3 mutants (R-HSA-9702614)
  quizartinib-resistant FLT3 mutants (R-HSA-9702620)
  sorafenib-resistant FLT3 mutants (R-HSA-9702624)
  sunitinib-resistant FLT3 mutants (R-HSA-9702632)
  tandutinib-resistant FLT3 mutants (R-HSA-9702636)
  linifanib-resistant FLT3 mutants (R-HSA-9702998)
  tamatinib-resistant FLT3 mutants (R-HSA-9703009)
  Signaling by FLT3 ITD and TKD mutants (R-HSA-9703648)
  Negative regulation of FLT3 (R-HSA-9706369)
  FLT3 signaling through SRC family kinases (R-HSA-9706374)
  FLT3 signaling by CBL mutants (R-HSA-9706377)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Gilteritinib	DMWQ4MZ	Acute myeloid leukaemia	2A60	Approved	[2]
Intedanib	DMSTA36	Colorectal cancer	2B91.Z	Approved	[3]
Lestaurtinib	DMQ2AIJ	Acute myeloid leukaemia	2A60	Approved (orphan drug)	[4], [5]
Midostaurin	DMI6E0R	Acute myeloid leukaemia	2A60	Approved	[1], [6]
Pexidartinib	DMS2J0Z	Tenosynovial giant cell tumour	2F7B	Approved	[7]
Ponatinib	DMYGJQO	Acute lymphoblastic leukaemia	2A85	Approved	[8]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[9]

20 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AC220	DM8Y4JS	Acute myeloid leukaemia	2A60	Phase 3	[10], [11]
Pacritinib	DM1T6ZN	Myelofibrosis	2A20.2	Phase 3	[9]
BMS-690514	DMX302C	Chronic pain	MG30	Phase 2	[12]
CDX-301	DMKRFCO	Hematopoietic stem cell transplantation	QB63	Phase 2	[13]
Famitinib	DMSFWT7	Solid tumour/cancer	2A00-2F9Z	Phase 2	[14]
TAK-659	DMJH3U0	Diffuse large B-cell lymphoma	2A81	Phase 2	[10]
FF-10101	DM1XIMU	Acute myeloid leukaemia	2A60	Phase 1/2	[15]
HM43239	DMV1SDA	Acute myeloid leukaemia	2A60	Phase 1/2	[16]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[17]
SEL-24	DMH064K	Acute myeloid leukaemia	2A60	Phase 1/2	[10]
SEL24	DMD37Q5	Acute myeloid leukaemia	2A60	Phase 1/2	[18]
4SC-203	DM8XMPT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[19]
AMG 427	DMI7JO6	Acute myeloid leukaemia	2A60	Phase 1	[20]
FF-10101-01	DMS1O56	Acute myeloid leukaemia	2A60	Phase 1	[10]
FN-1501	DM7BMD6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[21]
IMC-EB10	DMCZQNJ	Acute myeloid leukaemia	2A60	Phase 1	[22], [23]
Ki23819	DMIAVBL	Solid tumour/cancer	2A00-2F9Z	Phase 1	[24]
KW-2449	DMFO7RP	Acute myeloid leukaemia	2A60	Phase 1	[25]
MRX-2843	DMM5N8P	Solid tumour/cancer	2A00-2F9Z	Phase 1	[26]
SKI-G-801	DM4I92Z	Acute myeloid leukaemia	2A60	Phase 1	[27]

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Carboxamide derivative 4	DMU5GKC	N. A.	N. A.	Patented	[28]
Pyridine derivative 18	DMBZMYT	N. A.	N. A.	Patented	[28]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tandutinib	DMNU2MH	Anaplastic mixed oligoastrocytoma	2A00.0Y	Discontinued in Phase 2	[1], [29]
AG1295	DMT10C2	N. A.	N. A.	Terminated	[31]
SU5614	DMO9UCK	Airway inflammation	CA05	Terminated	[32]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MC-2001	DMBT2RJ	leukaemia	2A60-2B33	Preclinical	[30]

27 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(1H-indol-2-yl)(5-methoxy-1H-indol-2-yl)methanone	DM21CXZ	Discovery agent	N.A.	Investigative	[33]
(1H-indol-2-yl)(5-phenoxy-1H-indol-2-yl)methanone	DM94XJ2	Discovery agent	N.A.	Investigative	[33]
(1H-indol-2-yl)(6-methoxy-1H-indol-2-yl)methanone	DM7KDNM	Discovery agent	N.A.	Investigative	[33]
(5-fluoro-1H-indol-2-yl)-(1H-indol-2-yl)methanone	DMIV4BU	Discovery agent	N.A.	Investigative	[33]
(5-hydroxy-1H-indol-2-yl)(1H-indol-2-yl)methanone	DMPBNYM	Discovery agent	N.A.	Investigative	[33]
(benzo[b]furan-2-yl)-(1H-indol-2-yl)methanone	DME80RK	Discovery agent	N.A.	Investigative	[31]
2-(3,4-dimethoxybenzamido)thiophene-3-carboxamide	DM3S26I	Discovery agent	N.A.	Investigative	[34]
4-(4-aminophenyl)-1H-indazol-3yl-amine	DMK1IWD	Discovery agent	N.A.	Investigative	[35]
AKN-028	DMANYU5	Acute myeloid leukaemia	2A60	Investigative	[9]
AST-487	DME76KU	Discovery agent	N.A.	Investigative	[36]
Bis(5-acetoxybenzo[b]furan-2-yl)methanone	DM36VKH	Discovery agent	N.A.	Investigative	[31]
Bis(5-aminobenzo[b]furan-2-yl)methanone	DMHRGTY	Discovery agent	N.A.	Investigative	[31]
Bis(5-hydroxybenzo[b]furan-2-yl)methanone	DMGRKDP	Discovery agent	N.A.	Investigative	[31]
Bis(6-hydroxybenzo[b]furan-2-yl)methanone	DMRGNSQ	Discovery agent	N.A.	Investigative	[31]
Bis(benzo[b]furan-2-yl)methanone	DMK2ZG4	Discovery agent	N.A.	Investigative	[31]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone	DMTSEXB	Discovery agent	N.A.	Investigative	[33]
Di(1H-indol-2-yl)methanone	DM3DR6J	Discovery agent	N.A.	Investigative	[33]
G749	DMC7HIS	Discovery agent	N.A.	Investigative	[37]
GTP-14564	DMW23Y9	Discovery agent	N.A.	Investigative	[38]
IN1479	DM4JNUH	Discovery agent	N.A.	Investigative	[39]
JNJ-28312141	DMCMH7O	Discovery agent	N.A.	Investigative	[40]
N-[4-(3-amino-1H-indazol-4-yl)phenyl]benzamide	DMLV18K	Discovery agent	N.A.	Investigative	[35]
PMID21982499C14k	DM0VOXN	Discovery agent	N.A.	Investigative	[41]
PMID22765894C8h	DMH5RFU	Discovery agent	N.A.	Investigative	[42]
PMID24900538C2c	DM5PATM	Discovery agent	N.A.	Investigative	[43]
TCS-359	DMH6UN8	Discovery agent	N.A.	Investigative	[34]
URMC-099	DMCJXWK	Discovery agent	N.A.	Investigative	[44]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	2.11E-01	-0.05	-0.16
Psoriasis	EA90	Skin	9.51E-04	0.04	0.11
Glioma	2C82	Brainstem tissue	4.98E-01	-0.49	-0.75
Glioma	2C82	White matter	1.15E-01	-0.35	-0.75
Acute myelocytic leukaemia	2C82	Bone marrow	2.64E-120	3.41	4.96
Colon cancer	2C82	Colon tissue	1.53E-13	-0.21	-0.78
Breast cancer	2C82	Breast tissue	1.20E-11	0.16	0.33
Myelodysplastic syndrome	2C82	Bone marrow	1.71E-02	-0.34	-0.58
Thyroid cancer	2C82	Thyroid	5.04E-01	0.13	0.19
Renal cancer	2C82	Kidney	1.36E-01	-0.25	-0.82
Gastric cancer	2C82	Gastric tissue	7.64E-01	-0.27	-0.56
Head and neck cancer	2C82	Head and neck tissue	1.09E-03	0.09	0.33

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