Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMSRYMK)

• DOT Name: Receptor-type tyrosine-protein kinase FLT3 (FLT3)
• Synonyms: EC 2.7.10.1; FL cytokine receptor; Fetal liver kinase-2; FLK-2; Fms-like tyrosine kinase 3; FLT-3; Stem cell tyrosine kinase 1; STK-1; CD antigen CD135
• Gene Name: FLT3
• UniProt ID: FLT3_HUMAN
• PDB ID: 1RJB; 3QS7; 3QS9; 4RT7; 4XUF; 5X02; 6IL3; 6JQR; 7QDP; 7ZV9
• EC Number: 2.7.10.1
• Pfam ID: PF00047 ; PF07714
• 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 a 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.
• Tissue Specificity: Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hematopoietic cell lineage (hsa04640)
  Pathways in cancer (hsa05200)
  Transcriptio.l 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 DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sorafenib	DMS8IFC	Approved	Receptor-type tyrosine-protein kinase FLT3 (FLT3) increases the response to substance of Sorafenib.	[19]
Midostaurin	DMI6E0R	Approved	Receptor-type tyrosine-protein kinase FLT3 (FLT3) decreases the response to substance of Midostaurin.	[20]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[2]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[4]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[6]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[7]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[9]
Romiplostim	DM3U7SZ	Approved	Romiplostim decreases the activity of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[11]
Venetoclax	DM8I94Y	Approved	Venetoclax decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[12]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[13]
PU-H71	DMIYHAW	Phase 1	PU-H71 decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[12]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[16]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[17]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[18]

7 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the phosphorylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[5]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the phosphorylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[8]
Romidepsin	DMT5GNL	Approved	Romidepsin decreases the phosphorylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[10]
AC220	DM8Y4JS	Approved	AC220 decreases the phosphorylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the phosphorylation of Receptor-type tyrosine-protein kinase FLT3 (FLT3).	[15]

References

• [1] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [2] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [3] Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation. Clin Cancer Res. 2006 Nov 15;12(22):6817-25. doi: 10.1158/1078-0432.CCR-06-1354.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [6] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [7] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [8] Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. Clin Cancer Res. 2010 Feb 15;16(4):1149-58. doi: 10.1158/1078-0432.CCR-09-2416. Epub 2010 Feb 9.
• [9] Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood. 2016 Jun 9;127(23):2890-902. doi: 10.1182/blood-2015-11-683581. Epub 2016 Apr 20.
• [10] Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3. Arch Toxicol. 2022 Jan;96(1):177-193. doi: 10.1007/s00204-021-03174-1. Epub 2021 Oct 19.
• [11] SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood. 2003 Aug 1;102(3):795-801. doi: 10.1182/blood-2002-10-3023. Epub 2003 Mar 20.
• [12] HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. Curr Issues Mol Biol. 2023 Aug 23;45(9):7011-7026. doi: 10.3390/cimb45090443.
• [13] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther. 2011 Jun;10(6):1028-35. doi: 10.1158/1535-7163.MCT-10-1044. Epub 2011 Apr 11.
• [16] Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
• [17] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [18] Arsenic trioxide induces autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD acute myeloid leukemia cells. J Cancer. 2020 Mar 13;11(12):3476-3482. doi: 10.7150/jca.29751. eCollection 2020.
• [19] Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. Cancer Lett. 2013 Feb 1;329(1):45-58. doi: 10.1016/j.canlet.2012.09.020. Epub 2012 Oct 2.
• [20] Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells. PLoS One. 2011;6(9):e25351. doi: 10.1371/journal.pone.0025351. Epub 2011 Sep 28.