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]
• 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

9 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Gilteritinib	DMTI0ZO	Acute myeloid leukaemia	2A60	Approved	[2]
Intedanib	DMSTA36	Colorectal cancer	2B91.Z	Approved	[3]
Lestaurtinib	DMQ2AIJ	Acute myeloid leukaemia	2A60	Approved (orphan drug)	[4]
Midostaurin	DMI6E0R	Acute myeloid leukaemia	2A60	Approved	[1]
Pacritinib	DM1T6ZN	Myelofibrosis	2A20.2	Approved	[5]
Pexidartinib	DMS2J0Z	Tenosynovial giant cell tumour	2F7B	Approved	[6]
Ponatinib	DMYGJQO	Acute lymphoblastic leukaemia	2A85	Approved	[7]
Quizartinib	DM8Y4JS	Acute myeloid leukaemia	2A60	Approved	[8]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[5]

18 Clinical Trial Drug(s) Targeting This DTT

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

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	[24]
Pyridine derivative 18	DMBZMYT	N. A.	N. A.	Patented	[24]

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]
AG1295	DMT10C2	N. A.	N. A.	Terminated	[26]
SU5614	DMO9UCK	Airway inflammation	CA05	Terminated	[27]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MC-2001	DMBT2RJ	leukaemia	2A60-2B33	Preclinical	[25]

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	[28]
(1H-indol-2-yl)(5-phenoxy-1H-indol-2-yl)methanone	DM94XJ2	Discovery agent	N.A.	Investigative	[28]
(1H-indol-2-yl)(6-methoxy-1H-indol-2-yl)methanone	DM7KDNM	Discovery agent	N.A.	Investigative	[28]
(5-fluoro-1H-indol-2-yl)-(1H-indol-2-yl)methanone	DMIV4BU	Discovery agent	N.A.	Investigative	[28]
(5-hydroxy-1H-indol-2-yl)(1H-indol-2-yl)methanone	DMPBNYM	Discovery agent	N.A.	Investigative	[28]
(benzo[b]furan-2-yl)-(1H-indol-2-yl)methanone	DME80RK	Discovery agent	N.A.	Investigative	[26]
2-(3,4-dimethoxybenzamido)thiophene-3-carboxamide	DM3S26I	Discovery agent	N.A.	Investigative	[29]
4-(4-aminophenyl)-1H-indazol-3yl-amine	DMK1IWD	Discovery agent	N.A.	Investigative	[30]
AKN-028	DMANYU5	Acute myeloid leukaemia	2A60	Investigative	[5]
AST-487	DME76KU	Discovery agent	N.A.	Investigative	[31]
Bis(5-acetoxybenzo[b]furan-2-yl)methanone	DM36VKH	Discovery agent	N.A.	Investigative	[26]
Bis(5-aminobenzo[b]furan-2-yl)methanone	DMHRGTY	Discovery agent	N.A.	Investigative	[26]
Bis(5-hydroxybenzo[b]furan-2-yl)methanone	DMGRKDP	Discovery agent	N.A.	Investigative	[26]
Bis(6-hydroxybenzo[b]furan-2-yl)methanone	DMRGNSQ	Discovery agent	N.A.	Investigative	[26]
Bis(benzo[b]furan-2-yl)methanone	DMK2ZG4	Discovery agent	N.A.	Investigative	[26]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone	DMTSEXB	Discovery agent	N.A.	Investigative	[28]
Di(1H-indol-2-yl)methanone	DM3DR6J	Discovery agent	N.A.	Investigative	[28]
G749	DMC7HIS	Discovery agent	N.A.	Investigative	[32]
GTP-14564	DMW23Y9	Discovery agent	N.A.	Investigative	[33]
IN1479	DM4JNUH	Discovery agent	N.A.	Investigative	[34]
JNJ-28312141	DMCMH7O	Discovery agent	N.A.	Investigative	[35]
N-[4-(3-amino-1H-indazol-4-yl)phenyl]benzamide	DMLV18K	Discovery agent	N.A.	Investigative	[30]
PMID21982499C14k	DM0VOXN	Discovery agent	N.A.	Investigative	[36]
PMID22765894C8h	DMH5RFU	Discovery agent	N.A.	Investigative	[37]
PMID24900538C2c	DM5PATM	Discovery agent	N.A.	Investigative	[38]
TCS-359	DMH6UN8	Discovery agent	N.A.	Investigative	[29]
URMC-099	DMCJXWK	Discovery agent	N.A.	Investigative	[39]

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

References

• [1] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [2] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [3] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [4] Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with ... Blood. 2008 Jun 15;111(12):5663-71.
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1807).
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2. J Pharm Sci. 2010 Aug;99(8):3579-93.
• [10] Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers. Bone Marrow Transplant. 2015 Jul;50(7):924-30.
• [11] Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
• [12] A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations. Blood. 2018 Jan 25;131(4):426-438.
• [13] Clinical pipeline report, company report or official report of Hanmi Pharmaceutical.
• [14] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [15] A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia. Oncotarget. 2018 Mar 30;9(24):16917-16931.
• [16] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [17] Clinical pipeline report, company report or official report of Amgen.
• [18] Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J Med Chem. 2018 Feb 22;61(4):1499-1518.
• [19] IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples. Cancer Res. 2006 May 1;66(9):4843-51.
• [20] Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase. Leukemia. 2005 Jun;19(6):930-5.
• [21] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17.
• [22] The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI Insight. 2016 Mar;1(3):e85630.
• [23] Clinical pipeline report, company report or official report of Genosco.
• [24] RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
• [25] Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003 Oct;17(10):1961-6.
• [26] Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones. Bioorg Med Chem. 2007 Mar 1;15(5):2187-97.
• [27] FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res. 2009 Apr 1;69(7):3032-41.
• [28] Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2006 Jun 1;49(11):3101-15.
• [29] Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3282-6.
• [30] Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted ... J Med Chem. 2007 Apr 5;50(7):1584-97.
• [31] Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.
• [32] G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. Blood. 2014 Apr 3;123(14):2209-19.
• [33] Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosin... J Biol Chem. 2003 Aug 29;278(35):32892-8.
• [34] Aromatic interactions with phenylalanine 691 and cysteine 828: a concept for FMS-like tyrosine kinase-3 inhibition. Application to the discovery of a new class of potential antileukemia agents. J MedChem. 2006 Jul 27;49(15):4451-4.
• [35] JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia. Mol Cancer Ther. 2009 Nov;8(11):3151-61.
• [36] 7-(4H-1,2,4-Triazol-3-yl)benzo[c][2,6]naphthyridines: a novel class of Pim kinase inhibitors with potent cell antiproliferative activity. Bioorg Med Chem Lett. 2011 Nov 15;21(22):6687-92.
• [37] The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
• [38] Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett. 2012 Jul 26;3(9):705-9.
• [39] Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48.