Target Information

Target General Infomation
Target ID
T74312
Former ID
TTDS00090
Target Name
FL cytokine receptor
Gene Name
FLT3
Synonyms
CD135 antigen; FLT3 tyrosine kinase ; Receptor tyrosine kinase FLT3; STK-1; Stem cell tyrosine kinase 1; Tyrosine-protein kinase receptor FLT3; FLT3
Target Type
Successful
Disease Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Airway inflammation [ICD9: 460-519; ICD10: J00-J99]
Alzheimer disease [ICD9: 331; ICD10: G30]
Acute myeloid leukemia; Prostate cancer; Pancreatic cancer [ICD9: 140-199, 140-229, 157, 205.0, 210-229; ICD10: C25, C92.0, D10-D36, D3A]
Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Breast cancer; Colorectal cancer [ICD9: 153, 154, 174, 175; ICD10: C18-C21, C50]
Colon cancer; Breast cancer; CLL; AML; GIST [ICD9: 140-199, 150-159, 200, 202, 202.8, 204.1, 205.0, 210-229; ICD10: C00-C75, C15-C26, C7A, C7B, C81-C86, C82-C85, C91.1, C92.0, D10-D36, D3A]
Chronic pain [ICD9: 338.2,780; ICD10: R52.1-R52.2, G89]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Cancer; Hematopoietic stem cell transplantation [ICD9:140-229; ICD10: C00-C96, Z00-Z99]
Glioblatoma; Gliosarcoma; Anaplastic mixed oligoastrocytoma [ICD9: 191; ICD10: C71]
Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Leukemia [ICD9: 208.9; ICD10: C90-C95]
Myelofibrosis [ICD9: 208.9, 289.83, 709.2; ICD10: C94.4, D47.4]
Myeloid leukemia [ICD9: 208.9; ICD10: C92]
Psoriasis [ICD9: 696; ICD10: L40]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
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
Target Validation
T74312
UniProt ID
P36888
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
Structure
1RJB; 3QS7; 3QS9
Drugs and Mode of Action
Drug(s) Midostaurin Drug Info Approved Acute myeloid leukemia [1]
Ponatinib Drug Info Approved Acute lymphoblastic leukemia [2], [3]
Lestaurtinib Drug Info Approved (orphan drug) Acute myeloid leukemia [4], [5]
Lestaurtinib Drug Info Phase 3 Myeloid leukemia [4], [5]
Pacritinib Drug Info Phase 3 Myelofibrosis [6], [7], [8]
PLX-3397 Drug Info Phase 3 Alzheimer disease [9]
Lestaurtinib Drug Info Phase 2/3 Psoriasis [10], [11], [5]
BMS-690514 Drug Info Phase 2 Chronic pain [12]
CDX-301 Drug Info Phase 2 Cancer; Hematopoietic stem cell transplantation [13]
Famitinib Drug Info Phase 2 Cancer [14], [15]
Lestaurtinib Drug Info Phase 2 Acute myeloid leukemia; Prostate cancer; Pancreatic cancer [4], [5]
Midostaurin Drug Info Phase 2 Colon cancer; Breast cancer; CLL; AML; GIST [16], [17]
MK-2461 Drug Info Phase 1/2 Alzheimer disease [18]
4SC-203 Drug Info Phase 1 Solid tumours [19]
IMC-EB10 Drug Info Phase 1 Acute myeloid leukemia [20]
Ki23819 Drug Info Phase 1 Cancer [21]
KW-2449 Drug Info Phase 1 Acute myeloid leukemia [22], [23]
Midostaurin Drug Info Phase 1 Breast cancer; Colorectal cancer [16], [17]
MC-2001 Drug Info Preclinical Leukemia [24]
Tandutinib Drug Info Discontinued in Phase 2 Glioblatoma; Gliosarcoma; Anaplastic mixed oligoastrocytoma [25], [26]
AG1295 Drug Info Terminated Discovery agent [27], [28]
SU5614 Drug Info Terminated Airway inflammation [29]
Inhibitor (1H-indol-2-yl)(5-methoxy-1H-indol-2-yl)methanone Drug Info [30]
(1H-indol-2-yl)(5-phenoxy-1H-indol-2-yl)methanone Drug Info [30]
(1H-indol-2-yl)(6-methoxy-1H-indol-2-yl)methanone Drug Info [30]
(5-fluoro-1H-indol-2-yl)-(1H-indol-2-yl)methanone Drug Info [30]
(5-hydroxy-1H-indol-2-yl)(1H-indol-2-yl)methanone Drug Info [30]
(benzo[b]furan-2-yl)-(1H-indol-2-yl)methanone Drug Info [31]
2-(3,4-dimethoxybenzamido)thiophene-3-carboxamide Drug Info [32]
4-(4-aminophenyl)-1H-indazol-3yl-amine Drug Info [33]
AG1295 Drug Info [31]
AKN-028 Drug Info [34]
AST-487 Drug Info [35]
Bis(5-acetoxybenzo[b]furan-2-yl)methanone Drug Info [31]
Bis(5-aminobenzo[b]furan-2-yl)methanone Drug Info [31]
Bis(5-hydroxybenzo[b]furan-2-yl)methanone Drug Info [31]
Bis(6-hydroxybenzo[b]furan-2-yl)methanone Drug Info [31]
Bis(benzo[b]furan-2-yl)methanone Drug Info [31]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone Drug Info [30]
BMS-690514 Drug Info [36]
CDX-301 Drug Info [37]
compound 14k Drug Info [38]
compound 2c Drug Info [39]
compound 8h Drug Info [40]
Di(1H-indol-2-yl)methanone Drug Info [30]
Famitinib Drug Info [14]
Flt-3 inhibitor II Drug Info [30]
G749 Drug Info [41]
GTP-14564 Drug Info [42]
IN1479 Drug Info [43]
JNJ-28312141 Drug Info [44]
Ki23819 Drug Info [45]
MC-2001 Drug Info [46]
Midostaurin Drug Info [47], [48]
MK-2461 Drug Info [18]
N-[4-(3-amino-1H-indazol-4-yl)phenyl]benzamide Drug Info [33]
PLX-3397 Drug Info [49]
SU5614 Drug Info [50]
Tandutinib Drug Info [47], [51]
TCS-359 Drug Info [32]
URMC-099 Drug Info [52]
Modulator 4SC-203 Drug Info [53]
Lestaurtinib Drug Info [10], [11]
Pacritinib Drug Info [34]
Ponatinib Drug Info [54]
Binder Dendrigen Drug Info [34]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Cytokine-cytokine receptor interaction
Hematopoietic cell lineage
Pathways in cancer
Transcriptional misregulation in cancer
Acute myeloid leukemia
Central carbon metabolism in cancer
References
REF 1Drugs@FDA (Edaravone)
REF 2Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
REF 3(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 4Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
REF 5(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 6ClinicalTrials.gov (NCT02055781) Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis With Thrombocytopenia. U.S. National Institutes of Health.
REF 7(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 8Clinical pipeline report, company report or official report of CTI BioPharma.
REF 9ClinicalTrials.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 10A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006 Nov 15;108(10):3262-70. Epub 2006 Jul 20.
REF 11Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008 Jun 15;111(12):5663-71. Epub 2007 Nov 5.
REF 12A 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 13ClinicalTrials.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 14Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
REF 15(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 16Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
REF 17(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: 5702).
REF 18MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
REF 192011 Pipeline of 4SC AG.
REF 20ClinicalTrials.gov (NCT00887926) Study of EB10 in Patients With Leukemia. U.S. National Institutes of Health.
REF 21Mol Cancer Ther. 2004 Dec;3(12):1639-49.KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth.
REF 22KW-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 23(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 24Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021088)
REF 25(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 26Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017148)
REF 27(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: 5914).
REF 28Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007894)
REF 29Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014776)
REF 30J Med Chem. 2006 Jun 1;49(11):3101-15.Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase.
REF 31Bioorg Med Chem. 2007 Mar 1;15(5):2187-97. Epub 2006 Dec 12.Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones.
REF 32Bioorg Med Chem Lett. 2006 Jun 15;16(12):3282-6. Epub 2006 Mar 31.Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3.
REF 33J Med Chem. 2007 Apr 5;50(7):1584-97. Epub 2007 Mar 8.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 receptor tyrosine kinase inhibitor.
REF 34(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 35Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.
REF 36Preclinical 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 37Efficacy 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 387-(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 39Discovery 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 40The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
REF 41G-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 42Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem. 2003 Aug 29;278(35):32892-8. Epub 2003 Jun 18.
REF 43Aromatic 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 44JNJ-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 45Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase. Leukemia. 2005 Jun;19(6):930-5.
REF 46Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003 Oct;17(10):1961-6.
REF 47A 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 48CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res. 2009 Apr 1;15(7):2238-47. Epub 2009 Mar 10.
REF 49National Cancer Institute Drug Dictionary (drug id 659167).
REF 50FMS-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. Epub 2009 Mar 24.
REF 51Clinical pipeline report, company report or official report of Takeda (2009).
REF 52Discovery, 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.
REF 53Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 54Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

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