Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXRAY6X)

• DOT Name: Granulocyte colony-stimulating factor receptor (CSF3R)
• Synonyms: G-CSF receptor; G-CSF-R; CD antigen CD114
• Gene Name: CSF3R
• Related Disease:
  Autosomal recessive severe congenital neutropenia due to CSF3R deficiency
  Hereditary neutrophilia
• UniProt ID: CSF3R_HUMAN
• PDB ID: 2D9Q
• Pfam ID: PF00041 ; PF06328
• Sequence:
  MARLGNCSLTWAALIILLLPGSLEECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEPQ
  ILWRLGAELQPGGRQQRLSDGTQESIITLPHLNHTQAFLSCCLNWGNSLQILDQVELRAG
  YPPAIPHNLSCLMNLTTSSLICQWEPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPK
  DGQSHCCIPRKHLLLYQNMGIWVQAENALGTSMSPQLCLDPMDVVKLEPPMLRTMDPSPE
  AAPPQAGCLQLCWEPWQPGLHINQKCELRHKPQRGEASWALVGPLPLEALQYELCGLLPA
  TAYTLQIRCIRWPLPGHWSDWSPSLELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVP
  LEEDSGRIQGYVVSWRPSGQAGAILPLCNTTELSCTFHLPSEAQEVALVAYNSAGTSRPT
  PVVFSESRGPALTRLHAMARDPHSLWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRME
  QNGRATGFLLKENIRPFQLYEIIVTPLYQDTMGPSQHVYAYSQEMAPSHAPELHLKHIGK
  TWAQLEWVPEPPELGKSPLTHYTIFWTNAQNQSFSAILNASSRGFVLHGLEPASLYHIHL
  MAASQAGATNSTVLTLMTLTPEGSELHIILGLFGLLLLLTCLCGTAWLCCSPNRKNPLWP
  SVPDPAHSSLGSWVPTIMEEDAFQLPGLGTPPITKLTVLEEDEKKPVPWESHNSSETCGL
  PTLVQTYVLQGDPRAVSTQPQSQSGTSDQVLYGQLLGSPTSPGPGHYLRCDSTQPLLAGL
  TPSPKSYENLWFQASPLGTLVTPAPSQEDDCVFGPLLNFPLLQGIRVHGMEALGSF
• Function: Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differientation and survival of cells along the neutrophilic lineage. In addition it may function in some adhesion or recognition events at the cell surface.
• Tissue Specificity: One or several isoforms have been found in myelogenous leukemia cell line KG-1, leukemia U-937 cell line, in bone marrow cells, placenta, and peripheral blood granulocytes. Isoform GCSFR-2 is found only in leukemia U-937 cells. Isoform GCSFR-3 is highly expressed in placenta.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  PI3K-Akt sig.ling pathway (hsa04151)
  JAK-STAT sig.ling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  Other interleukin signaling (R-HSA-449836)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive severe congenital neutropenia due to CSF3R deficiency	DIS3X9I0	Strong	Autosomal recessive	[1]
Hereditary neutrophilia	DISWTVMY	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Famotidine	DMRL3AB	Approved	Granulocyte colony-stimulating factor receptor (CSF3R) increases the Bone marrow failure ADR of Famotidine.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Granulocyte colony-stimulating factor receptor (CSF3R).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Granulocyte colony-stimulating factor receptor (CSF3R).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[10]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[11]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[14]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Granulocyte colony-stimulating factor receptor (CSF3R).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med. 2009 Aug 3;206(8):1701-7. doi: 10.1084/jem.20090693. Epub 2009 Jul 20.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [12] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [13] 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.
• [14] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [15] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.