Target General Infomation
Target ID
T74312 (Former ID: TTDS00090)
Target 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
Target Type
Successful target
[1]
Disease [+] 6 Target-related Diseases +
1 Acute myeloid leukaemia [ICD-11: 2A60]
2 Colorectal cancer [ICD-11: 2B91]
3 Human immunodeficiency virus disease [ICD-11: 1C60-1C62]
4 Idiopathic interstitial pneumonitis [ICD-11: CB03]
5 Mastocytosis [ICD-11: 2A21]
6 Mature B-cell lymphoma [ICD-11: 2A85]
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.
BioChemical Class
Kinase
UniProt ID
FLT3_HUMAN
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
Drugs and Modes of Action
Approved Drug(s) [+] 6 Approved Drugs +
1 Gilteritinib Drug Info Approved Acute myeloid leukaemia [2], [3]
2 Intedanib Drug Info Approved Colorectal cancer [4]
3 Midostaurin Drug Info Approved Acute myeloid leukaemia [5]
4 Ponatinib Drug Info Approved Acute lymphoblastic leukaemia [6], [7]
5 Zidovudine Drug Info Approved Human immunodeficiency virus infection [8], [9]
6 Lestaurtinib Drug Info Approved (orphan drug) Acute myeloid leukaemia [10], [11]
Clinical Trial Drug(s) [+] 14 Clinical Trial Drugs +
1 AC220 Drug Info Phase 3 leukaemia [12]
2 Pacritinib Drug Info Phase 3 Myelofibrosis [3], [13], [14], [15]
3 PLX-3397 Drug Info Phase 3 Alzheimer disease [16]
4 BMS-690514 Drug Info Phase 2 Chronic pain [17]
5 CDX-301 Drug Info Phase 2 Hematopoietic stem cell transplantation [18]
6 Famitinib Drug Info Phase 2 Solid tumour/cancer [19], [20]
7 TAK-659 Drug Info Phase 2 Diffuse large B-cell lymphoma [3]
8 MK-2461 Drug Info Phase 1/2 Alzheimer disease [21]
9 SEL-24 Drug Info Phase 1/2 Acute myeloid leukaemia [3]
10 4SC-203 Drug Info Phase 1 Solid tumour/cancer [22]
11 FF-10101-01 Drug Info Phase 1 Acute myeloid leukaemia [3]
12 IMC-EB10 Drug Info Phase 1 Acute myeloid leukaemia [23]
13 Ki23819 Drug Info Phase 1 Solid tumour/cancer [24]
14 KW-2449 Drug Info Phase 1 Acute myeloid leukaemia [25], [26]
Discontinued Drug(s) [+] 2 Discontinued Drugs +
1 Tandutinib Drug Info Discontinued in Phase 2 Anaplastic mixed oligoastrocytoma [27], [28]
2 SU5614 Drug Info Terminated Airway inflammation [30]
Preclinical Drug(s) [+] 1 Preclinical Drugs +
1 MC-2001 Drug Info Preclinical leukaemia [29]
Mode of Action [+] 3 Modes of Action +
Inhibitor [+] 46 Inhibitor drugs +
1 Gilteritinib Drug Info [2]
2 Intedanib Drug Info [4]
3 Midostaurin Drug Info [1], [33]
4 AC220 Drug Info [3], [36]
5 PLX-3397 Drug Info [37]
6 BMS-690514 Drug Info [38]
7 CDX-301 Drug Info [39]
8 Famitinib Drug Info [20]
9 TAK-659 Drug Info [3]
10 MK-2461 Drug Info [21]
11 SEL-24 Drug Info [3]
12 FF-10101-01 Drug Info [3]
13 Ki23819 Drug Info [43]
14 Carboxamide derivative 4 Drug Info [44]
15 Pyridine derivative 18 Drug Info [44]
16 Tandutinib Drug Info [1], [45]
17 MC-2001 Drug Info [46]
18 AG1295 Drug Info [47]
19 SU5614 Drug Info [48]
20 (1H-indol-2-yl)(5-methoxy-1H-indol-2-yl)methanone Drug Info [49]
21 (1H-indol-2-yl)(5-phenoxy-1H-indol-2-yl)methanone Drug Info [49]
22 (1H-indol-2-yl)(6-methoxy-1H-indol-2-yl)methanone Drug Info [49]
23 (5-fluoro-1H-indol-2-yl)-(1H-indol-2-yl)methanone Drug Info [49]
24 (5-hydroxy-1H-indol-2-yl)(1H-indol-2-yl)methanone Drug Info [49]
25 (benzo[b]furan-2-yl)-(1H-indol-2-yl)methanone Drug Info [47]
26 2-(3,4-dimethoxybenzamido)thiophene-3-carboxamide Drug Info [50]
27 4-(4-aminophenyl)-1H-indazol-3yl-amine Drug Info [51]
28 AKN-028 Drug Info [35]
29 AST-487 Drug Info [52]
30 Bis(5-acetoxybenzo[b]furan-2-yl)methanone Drug Info [47]
31 Bis(5-aminobenzo[b]furan-2-yl)methanone Drug Info [47]
32 Bis(5-hydroxybenzo[b]furan-2-yl)methanone Drug Info [47]
33 Bis(6-hydroxybenzo[b]furan-2-yl)methanone Drug Info [47]
34 Bis(benzo[b]furan-2-yl)methanone Drug Info [47]
35 Bis-(5-hydroxy-1H-indol-2-yl)-methanone Drug Info [49]
36 Di(1H-indol-2-yl)methanone Drug Info [49]
37 G749 Drug Info [53]
38 GTP-14564 Drug Info [54]
39 IN1479 Drug Info [55]
40 JNJ-28312141 Drug Info [56]
41 N-[4-(3-amino-1H-indazol-4-yl)phenyl]benzamide Drug Info [51]
42 PMID21982499C14k Drug Info [57]
43 PMID22765894C8h Drug Info [58]
44 PMID24900538C2c Drug Info [59]
45 TCS-359 Drug Info [50]
46 URMC-099 Drug Info [60]
Modulator [+] 4 Modulator drugs +
1 Lestaurtinib Drug Info [31], [32]
2 Ponatinib Drug Info [34]
3 Pacritinib Drug Info [35]
4 4SC-203 Drug Info [40]
Binder [+] 1 Binder drugs +
1 Zidovudine Drug Info [35]
Target Regulators
Target-regulating microRNAs
Target Profiles in Patients
Target Expression
 Profile (TEP)
Drug Resistance
 Mutation (DRM)
Target Affiliated Biological Pathways
KEGG Pathway [+] 6 KEGG Pathways +
1 Cytokine-cytokine receptor interaction
2 Hematopoietic cell lineage
3 Pathways in cancer
4 Transcriptional misregulation in cancer
5 Acute myeloid leukemia
6 Central carbon metabolism in cancer
Target-Related Models and Studies
Target Validation
References
REF 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.
REF 2 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
REF 3 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 4 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
REF 5 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018
REF 6 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. (Ligand id: 5890).
REF 7 Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
REF 8 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. (Ligand id: 4825).
REF 9 Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
REF 10 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. (Ligand id: 5672).
REF 11 Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
REF 12 ClinicalTrials.gov (NCT02039726) An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects. U.S. National Institutes of Health.
REF 13 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. (Ligand id: 7793).
REF 14 Clinical pipeline report, company report or official report of CTI BioPharma.
REF 15 ClinicalTrials.gov (NCT02055781) Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis With Thrombocytopenia. U.S. National Institutes of Health.
REF 16 ClinicalTrials.gov (NCT02371369) PLX3397 Phase 3 Study for Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCT-TS). U.S. National Institutes of Health.
REF 17 A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. Cancer Res. 2007 Jul 1;67(13):6253-62.
REF 18 ClinicalTrials.gov (NCT02129075) CDX-1401 and Poly-ICLC Vaccine Therapy With or Without CDX-301in Treating Patients With Stage IIB-IV Melanoma. U.S. National Institutes of Health.
REF 19 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. (Ligand id: 7886).
REF 20 Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
REF 21 MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
REF 22 2011 Pipeline of 4SC AG.
REF 23 ClinicalTrials.gov (NCT00887926) Study of EB10 in Patients With Leukemia. U.S. National Institutes of Health.
REF 24 KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther. 2004 Dec;3(12):1639-49.
REF 25 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. (Ligand id: 5691).
REF 26 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.
REF 27 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. (Ligand id: 5695).
REF 28 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017148)
REF 29 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021088)
REF 30 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014776)
REF 31 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.
REF 32 A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered f... Blood. 2006 Nov 15;108(10):3262-70.
REF 33 CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subt... Clin Cancer Res. 2009 Apr 1;15(7):2238-47.
REF 34 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 35 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).
REF 36 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 37 National Cancer Institute Drug Dictionary (drug id 659167).
REF 38 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.
REF 39 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.
REF 40 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 41 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.
REF 42 Targeting FMS-related tyrosine kinase receptor 3 with the human immunoglobulin G1 monoclonal antibody IMC-EB10. Cancer. 2010 Feb 15;116(4 Suppl):1013-7.
REF 43 Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase. Leukemia. 2005 Jun;19(6):930-5.
REF 44 RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
REF 45 Clinical pipeline report, company report or official report of Takeda (2009).
REF 46 Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003 Oct;17(10):1961-6.
REF 47 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.
REF 48 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.
REF 49 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.
REF 50 Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3282-6.
REF 51 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.
REF 52 Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.
REF 53 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.
REF 54 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.
REF 55 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.
REF 56 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.
REF 57 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.
REF 58 The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
REF 59 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.
REF 60 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.

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