Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRL6OSI)

• DOT Name: Tyrosine-protein kinase HCK (HCK)
• Synonyms: EC 2.7.10.2; Hematopoietic cell kinase; Hemopoietic cell kinase; p59-HCK/p60-HCK; p59Hck; p61Hck
• Gene Name: HCK
• Related Disease: Autoinflammation with pulmonary and cutaneous vasculitis
• UniProt ID: HCK_HUMAN
• PDB ID: 1AD5 ; 1BU1 ; 1QCF ; 2C0I ; 2C0O ; 2C0T ; 2HCK ; 2HK5 ; 2OI3 ; 2OJ2 ; 3HCK ; 3NHN ; 3RBB ; 3REA ; 3REB ; 3VRY ; 3VRZ ; 3VS0 ; 3VS1 ; 3VS2 ; 3VS3 ; 3VS4 ; 3VS5 ; 3VS6 ; 3VS7 ; 4HCK ; 4LUD ; 4LUE ; 4ORZ ; 4U5W ; 5H09 ; 5H0B ; 5H0E ; 5H0G ; 5H0H ; 5HCK ; 5NUH ; 5ZJ6 ; 8F2P
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MGGRSSCEDPGCPRDEERAPRMGCMKSKFLQVGGNTFSKTETSASPHCPVYVPDPTSTIK
  PGPNSHNSNTPGIREAGSEDIIVVALYDYEAIHHEDLSFQKGDQMVVLEESGEWWKARSL
  ATRKEGYIPSNYVARVDSLETEEWFFKGISRKDAERQLLAPGNMLGSFMIRDSETTKGSY
  SLSVRDYDPRQGDTVKHYKIRTLDNGGFYISPRSTFSTLQELVDHYKKGNDGLCQKLSVP
  CMSSKPQKPWEKDAWEIPRESLKLEKKLGAGQFGEVWMATYNKHTKVAVKTMKPGSMSVE
  AFLAEANVMKTLQHDKLVKLHAVVTKEPIYIITEFMAKGSLLDFLKSDEGSKQPLPKLID
  FSAQIAEGMAFIEQRNYIHRDLRAANILVSASLVCKIADFGLARVIEDNEYTAREGAKFP
  IKWTAPEAINFGSFTIKSDVWSFGILLMEIVTYGRIPYPGMSNPEVIRALERGYRMPRPE
  NCPEELYNIMMRCWKNRPEERPTFEYIQSVLDDFYTATESQYQQQP
• Function: Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.
• Tissue Specificity: Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway:
  FCGR activation (R-HSA-2029481)
  Regulation of signaling by CBL (R-HSA-912631)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  FLT3 signaling through SRC family kinases (R-HSA-9706374)
  Nef and signal transduction (R-HSA-164944)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoinflammation with pulmonary and cutaneous vasculitis	DISZTFMC	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Tyrosine-protein kinase HCK (HCK) affects the binding of Adenosine triphosphate.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tyrosine-protein kinase HCK (HCK).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein kinase HCK (HCK).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tyrosine-protein kinase HCK (HCK).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine-protein kinase HCK (HCK).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tyrosine-protein kinase HCK (HCK).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Tyrosine-protein kinase HCK (HCK).	[7]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Tyrosine-protein kinase HCK (HCK).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Tyrosine-protein kinase HCK (HCK).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tyrosine-protein kinase HCK (HCK).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Tyrosine-protein kinase HCK (HCK).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Tyrosine-protein kinase HCK (HCK).	[3]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the activity of Tyrosine-protein kinase HCK (HCK).	[13]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase HCK (HCK).	[15]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Tyrosine-protein kinase HCK (HCK).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tyrosine-protein kinase HCK (HCK).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Tyrosine-protein kinase HCK (HCK).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the phosphorylation of Tyrosine-protein kinase HCK (HCK).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tyrosine-protein kinase HCK (HCK).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the phosphorylation of Tyrosine-protein kinase HCK (HCK).	[17]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the phosphorylation of Tyrosine-protein kinase HCK (HCK).	[20]

References

• [1] Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders. Am J Hum Genet. 2019 Dec 5;105(6):1274-1285. doi: 10.1016/j.ajhg.2019.11.003. Epub 2019 Nov 27.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia. Leukemia. 2007 May;21(5):906-11. doi: 10.1038/sj.leu.2404615. Epub 2007 Mar 8.
• [8] 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.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Effects of resveratrol on gene expression in renal cell carcinoma. Cancer Biol Ther. 2004 Sep;3(9):882-8. doi: 10.4161/cbt.3.9.1056. Epub 2004 Sep 21.
• [13] Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative. J Biol Chem. 2021 Jan-Jun;296:100449. doi: 10.1016/j.jbc.2021.100449. Epub 2021 Feb 20.
• [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] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [16] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [17] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [20] The anti-inflammatory effect of 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol by targeting Lyn kinase in human neutrophils. Chem Biol Interact. 2015 Jul 5;236:90-101. doi: 10.1016/j.cbi.2015.05.004. Epub 2015 May 14.