Target Information

Target General Information

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

[+] 7 Target-related Diseases

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]

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.

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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

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T91AIW

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 7 Approved Drugs

Gilteritinib

Drug Info

Approved

Acute myeloid leukaemia

[2], [3]

Intedanib

Drug Info

Approved

Colorectal cancer

[4]

Midostaurin

Drug Info

Approved

Acute myeloid leukaemia

[5]

Pexidartinib

Drug Info

Approved

Tenosynovial giant cell tumour

[6]

Ponatinib

Drug Info

Approved

Acute lymphoblastic leukaemia

[7], [8]

Zidovudine

Drug Info

Approved

Human immunodeficiency virus infection

[9], [10]

Lestaurtinib

Drug Info

Approved (orphan drug)

Acute myeloid leukaemia

[11], [12]

Clinical Trial Drug(s)

[+] 20 Clinical Trial Drugs

AC220

Drug Info

Phase 3

leukaemia

[13]

Pacritinib

Drug Info

Phase 3

Myelofibrosis

[3], [14], [15], [16]

BMS-690514

Drug Info

Phase 2

Chronic pain

[17]

CDX-301

Drug Info

Phase 2

Hematopoietic stem cell transplantation

[18]

Famitinib

Drug Info

Phase 2

Solid tumour/cancer

[19], [20]

TAK-659

Drug Info

Phase 2

Diffuse large B-cell lymphoma

[3]

FF-10101

Drug Info

Phase 1/2

Acute myeloid leukaemia

[21]

HM43239

Drug Info

Phase 1/2

Acute myeloid leukaemia

[22]

MK-2461

Drug Info

Phase 1/2

Alzheimer disease

[23]

SEL-24

Drug Info

Phase 1/2

Acute myeloid leukaemia

[3]

SEL24

Drug Info

Phase 1/2

Acute myeloid leukaemia

[24]

4SC-203

Drug Info

Phase 1

Solid tumour/cancer

[25]

AMG 427

Drug Info

Phase 1

Acute myeloid leukaemia

[26]

FF-10101-01

Drug Info

Phase 1

Acute myeloid leukaemia

[3]

FN-1501

Drug Info

Phase 1

Solid tumour/cancer

[27]

IMC-EB10

Drug Info

Phase 1

Acute myeloid leukaemia

[28]

Ki23819

Drug Info

Phase 1

Solid tumour/cancer

[29]

KW-2449

Drug Info

Phase 1

Acute myeloid leukaemia

[30], [31]

MRX-2843

Drug Info

Phase 1

Solid tumour/cancer

[32]

SKI-G-801

Drug Info

Phase 1

Acute myeloid leukaemia

[33]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

Tandutinib

Drug Info

Discontinued in Phase 2

Anaplastic mixed oligoastrocytoma

[34], [35]

SU5614

Drug Info

Terminated

Airway inflammation

[37]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

MC-2001

Drug Info

Preclinical

leukaemia

[36]

Mode of Action

[+] 3 Modes of Action

Inhibitor

[+] 53 Inhibitor drugs

Gilteritinib

Drug Info

[2]

Intedanib

Drug Info

[4]

Midostaurin

Drug Info

[1], [40]

Pexidartinib

Drug Info

[6]

AC220

Drug Info

[3], [43]

BMS-690514

Drug Info

[44]

CDX-301

Drug Info

[45]

Famitinib

Drug Info

[20]

TAK-659

Drug Info

[3]

FF-10101

Drug Info

[46]

HM43239

Drug Info

[47]

MK-2461

Drug Info

[23]

SEL-24

Drug Info

[3]

SEL24

Drug Info

[48]

AMG 427

Drug Info

[50]

FF-10101-01

Drug Info

[3]

FN-1501

Drug Info

[51]

Ki23819

Drug Info

[54]

MRX-2843

Drug Info

[55]

SKI-G-801

Drug Info

[56]

Carboxamide derivative 4

Drug Info

[57]

Pyridine derivative 18

Drug Info

[57]

Tandutinib

Drug Info

[1], [58]

MC-2001

Drug Info

[59]

AG1295

Drug Info

[60]

SU5614

Drug Info

[61]

(1H-indol-2-yl)(5-methoxy-1H-indol-2-yl)methanone

Drug Info

[62]

(1H-indol-2-yl)(5-phenoxy-1H-indol-2-yl)methanone

Drug Info

[62]

(1H-indol-2-yl)(6-methoxy-1H-indol-2-yl)methanone

Drug Info

[62]

(5-fluoro-1H-indol-2-yl)-(1H-indol-2-yl)methanone

Drug Info

[62]

(5-hydroxy-1H-indol-2-yl)(1H-indol-2-yl)methanone

Drug Info

[62]

(benzo[b]furan-2-yl)-(1H-indol-2-yl)methanone

Drug Info

[60]

2-(3,4-dimethoxybenzamido)thiophene-3-carboxamide

Drug Info

[63]

4-(4-aminophenyl)-1H-indazol-3yl-amine

Drug Info

[64]

AKN-028

Drug Info

[42]

AST-487

Drug Info

[65]

Bis(5-acetoxybenzo[b]furan-2-yl)methanone

Drug Info

[60]

Bis(5-aminobenzo[b]furan-2-yl)methanone

Drug Info

[60]

Bis(5-hydroxybenzo[b]furan-2-yl)methanone

Drug Info

[60]

Bis(6-hydroxybenzo[b]furan-2-yl)methanone

Drug Info

[60]

Bis(benzo[b]furan-2-yl)methanone

Drug Info

[60]

Bis-(5-hydroxy-1H-indol-2-yl)-methanone

Drug Info

[62]

Di(1H-indol-2-yl)methanone

Drug Info

[62]

G749

Drug Info

[66]

GTP-14564

Drug Info

[67]

IN1479

Drug Info

[68]

JNJ-28312141

Drug Info

[69]

N-[4-(3-amino-1H-indazol-4-yl)phenyl]benzamide

Drug Info

[64]

PMID21982499C14k

Drug Info

[70]

PMID22765894C8h

Drug Info

[71]

PMID24900538C2c

Drug Info

[72]

TCS-359

Drug Info

[63]

URMC-099

Drug Info

[73]

Modulator

[+] 4 Modulator drugs

Lestaurtinib

Drug Info

[38], [39]

Ponatinib

Drug Info

[41]

Pacritinib

Drug Info

[42]

4SC-203

Drug Info

[49]

Binder

[+] 1 Binder drugs

Zidovudine

Drug Info

[42]

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-regulating microRNAs

Target-regulating microRNAs Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 6 KEGG Pathways

Cytokine-cytokine receptor interaction

Hematopoietic cell lineage

Pathways in cancer

Transcriptional misregulation in cancer

Acute myeloid leukemia

Central carbon metabolism in cancer

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

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

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019

REF 7

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 8

Nat Rev Drug Discov. 2013 Feb;12(2):87-90.

REF 9

REF 10

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 11

REF 12

Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.

REF 13

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 14

REF 15

Clinical pipeline report, company report or official report of CTI BioPharma.

REF 16

ClinicalTrials.gov (NCT02055781) Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis With Thrombocytopenia. 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

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

ClinicalTrials.gov (NCT03194685) Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia. U.S. National Institutes of Health.

REF 22

ClinicalTrials.gov (NCT03850574) Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM43239 in Patients With Relapsed or Refractory Acute Myeloid Leukemia. U.S. National Institutes of Health.

REF 23

MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.

REF 24

ClinicalTrials.gov (NCT03008187) SEL24/MEN1703 in Patients With Acute Myeloid Leukemia. U.S. National Institutes of Health.

REF 25

2011 Pipeline of 4SC AG.

REF 26

ClinicalTrials.gov (NCT03541369) Safety, Tolerability, PK, PD, and Efficacy of AMG 427 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (20170528). U.S. National Institutes of Health.

REF 27

ClinicalTrials.gov (NCT03690154) A Phase 1 Study to Evaluate FN-1501 Monotherapy in Patients With Advanced Solid Tumors and R/R AML. U.S. National Institutes of Health.

REF 28

ClinicalTrials.gov (NCT00887926) Study of EB10 in Patients With Leukemia. U.S. National Institutes of Health.

REF 29

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 30

REF 31

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 32

ClinicalTrials.gov (NCT03510104) Pharmacokinetic and Safety Study of MRX-2843 in Adults With Relapsed/Refractory Advanced and/or Metastatic Solid Tumors. U.S. National Institutes of Health.

REF 33

ClinicalTrials.gov (NCT03564288) Study to Find a Safe and Effective Dose of SKI-G-801 in the Treatment of Patients With Acute Myeloid Leukemia (AML). U.S. National Institutes of Health.

REF 34

REF 35

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 36

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 37

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 38

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 39

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 40

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 41

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 42

REF 43

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 44

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 45

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 46

A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations. Blood. 2018 Jan 25;131(4):426-438.

REF 47

Clinical pipeline report, company report or official report of Hanmi Pharmaceutical.

REF 48

A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia. Oncotarget. 2018 Mar 30;9(24):16917-16931.

REF 49

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 50

Clinical pipeline report, company report or official report of Amgen.

REF 51

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.

REF 52

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 53

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 54

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase. Leukemia. 2005 Jun;19(6):930-5.

REF 55

The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI Insight. 2016 Mar;1(3):e85630.

REF 56

Clinical pipeline report, company report or official report of Genosco.

REF 57

RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.

REF 58

Clinical pipeline report, company report or official report of Takeda (2009).

REF 59

Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003 Oct;17(10):1961-6.

REF 60

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 61

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 62

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 63

Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3282-6.

REF 64

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 65

Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.

REF 66

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 67

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 68

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 69

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 70

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 71

The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.

REF 72

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 73

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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