Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOYSD1R)

• DOT Name: Crk-like protein (CRKL)
• Gene Name: CRKL
• Related Disease:
  Breast carcinoma
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Velocardiofacial syndrome
  Acute lymphocytic leukaemia
  Advanced cancer
  Aerodigestive tract cancer
  Angiosarcoma
  Bladder cancer
  Breast neoplasm
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Chronic graft versus host disease
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  DiGeorge syndrome
  Endometrial carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Leukemia
  Lung cancer
  Metastatic malignant neoplasm
  Neoplasm
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Rhabdomyosarcoma
  Tetralogy of fallot
  Trichohepatoenteric syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Laryngeal squamous cell carcinoma
  Lung carcinoma
  Shprintzen-Goldberg syndrome
  leukaemia
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Paramyotonia congenita of Von Eulenburg
  Rheumatoid arthritis
  Thyroid gland papillary carcinoma
  Congenital heart disease
• UniProt ID: CRKL_HUMAN
• PDB ID: 2BZX; 2BZY; 2DBK; 2EO3; 2LQN; 2LQW
• Pfam ID: PF00017 ; PF00018 ; PF07653
• Sequence:
  MSSARFDSSDRSAWYMGPVSRQEAQTRLQGQRHGMFLVRDSSTCPGDYVLSVSENSRVSH
  YIINSLPNRRFKIGDQEFDHLPALLEFYKIHYLDTTTLIEPAPRYPSPPMGSVSAPNLPT
  AEDNLEYVRTLYDFPGNDAEDLPFKKGEILVIIEKPEEQWWSARNKDGRVGMIPVPYVEK
  LVRSSPHGKHGNRNSNSYGIPEPAHAYAQPQTTTPLPAVSGSPGAAITPLPSTQNGPVFA
  KAIQKRVPCAYDKTALALEVGDIVKVTRMNINGQWEGEVNGRKGLFPFTHVKIFDPQNPD
  ENE
• Function: May mediate the transduction of intracellular signals.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Rap1 sig.ling pathway (hsa04015)
  Chemokine sig.ling pathway (hsa04062)
  Efferocytosis (hsa04148)
  Focal adhesion (hsa04510)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Neurotrophin sig.ling pathway (hsa04722)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  Growth hormone synthesis, secretion and action (hsa04935)
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
  Yersinia infection (hsa05135)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  MicroR.s in cancer (hsa05206)
  Re.l cell carcinoma (hsa05211)
  Chronic myeloid leukemia (hsa05220)
• Reactome Pathway:
  Downstream signal transduction (R-HSA-186763)
  MET activates RAP1 and RAC1 (R-HSA-8875555)
  MET receptor recycling (R-HSA-8875656)
  Erythropoietin activates RAS (R-HSA-9027284)
  Regulation of signaling by CBL (R-HSA-912631)
  Frs2-mediated activation (R-HSA-170968)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[3]
Velocardiofacial syndrome	DISOSBTY	Definitive	Biomarker	[4]
Acute lymphocytic leukaemia	DISPX75S	Strong	Posttranslational Modification	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Aerodigestive tract cancer	DIS3AOQ7	Strong	Biomarker	[7]
Angiosarcoma	DISIYS9W	Strong	Genetic Variation	[8]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[10]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Chronic graft versus host disease	DIS1MM9J	Strong	Biomarker	[11]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[12]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[15]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[9]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[17]
Prostate cancer	DISF190Y	Strong	Biomarker	[18]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[18]
Rhabdomyosarcoma	DISNR7MS	Strong	Biomarker	[9]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[19]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[19]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[20]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[15]
Shprintzen-Goldberg syndrome	DISQH6P3	moderate	Biomarker	[12]
leukaemia	DISS7D1V	Limited	Biomarker	[6]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[21]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[21]
Paramyotonia congenita of Von Eulenburg	DISXYDU9	Limited	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[23]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[22]
Congenital heart disease	DISQBA23	No Known	Unknown	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Crk-like protein (CRKL).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Crk-like protein (CRKL).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Crk-like protein (CRKL).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Crk-like protein (CRKL).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Crk-like protein (CRKL).	[37]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Crk-like protein (CRKL).	[38]

8 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 Crk-like protein (CRKL).	[28]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Crk-like protein (CRKL).	[29]
Imatinib	DM7RJXL	Approved	Imatinib decreases the phosphorylation of Crk-like protein (CRKL).	[30]
Nilotinib	DM7HXWT	Approved	Nilotinib decreases the phosphorylation of Crk-like protein (CRKL).	[31]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Crk-like protein (CRKL).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Crk-like protein (CRKL).	[34]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the phosphorylation of Crk-like protein (CRKL).	[35]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the phosphorylation of Crk-like protein (CRKL).	[39]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Crk-like protein (CRKL).	[33]

References

• [1] Increased Soluble CrkL in Serum of Breast Cancer Patients Is Associated with Advanced Disease.Cancers (Basel). 2019 Jul 9;11(7):961. doi: 10.3390/cancers11070961.
• [2] Crk-like adapter protein is required for TGF--induced AKT and ERK-signaling pathway in epithelial ovarian carcinomas.Tumour Biol. 2015 Feb;36(2):915-9. doi: 10.1007/s13277-014-2724-0. Epub 2014 Oct 12.
• [3] CRKL mediates EML4-ALK signaling and is a potential therapeutic target for ALK-rearranged lung adenocarcinoma.Oncotarget. 2016 May 17;7(20):29199-210. doi: 10.18632/oncotarget.8638.
• [4] Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome.Dev Cell. 2006 Jan;10(1):81-92. doi: 10.1016/j.devcel.2005.12.002.
• [5] Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia.Blood. 1994 Sep 15;84(6):1731-6.
• [6] CRKL regulates alternative splicing of cancer-related genes in cervical cancer samples and HeLa cell.BMC Cancer. 2019 May 27;19(1):499. doi: 10.1186/s12885-019-5671-8.
• [7] Downregulation of CRKL expression can inhibit tumorigenesis in colon cancer.Front Biosci (Landmark Ed). 2014 Jan 1;19(3):528-34. doi: 10.2741/4223.
• [8] Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway.Oncotarget. 2015 Nov 3;6(34):36041-52. doi: 10.18632/oncotarget.5936.
• [9] The role of CT10 regulation of kinase-like in cancer.Future Oncol. 2014 Dec;10(16):2687-97. doi: 10.2217/fon.14.199.
• [10] Overexpression of CRKL correlates with poor prognosis and cell proliferation in non-small cell lung cancer.Mol Carcinog. 2013 Nov;52(11):890-9. doi: 10.1002/mc.21935. Epub 2012 Jun 29.
• [11] Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients.Blood. 2018 Apr 12;131(15):1743-1754. doi: 10.1182/blood-2017-08-800623. Epub 2018 Jan 18.
• [12] 22q11.2 duplications in a UK cohort with bladder exstrophy-epispadias complex.Am J Med Genet A. 2019 Mar;179(3):404-409. doi: 10.1002/ajmg.a.61032. Epub 2019 Jan 9.
• [13] CRKL overexpression promotes cell proliferation and inhibits apoptosis in endometrial carcinoma.Oncol Lett. 2017 Jan;13(1):51-56. doi: 10.3892/ol.2016.5394. Epub 2016 Nov 17.
• [14] miR-429 suppresses tumor migration and invasion by targeting CRKL in hepatocellular carcinoma via inhibiting Raf/MEK/ERK pathway and epithelial-mesenchymal transition.Sci Rep. 2018 Feb 5;8(1):2375. doi: 10.1038/s41598-018-20258-8.
• [15] CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation.Lung Cancer. 2014 Aug;85(2):147-51. doi: 10.1016/j.lungcan.2014.05.018. Epub 2014 Jun 2.
• [16] The microRNA-200/Zeb1 axis regulates ECM-dependent 1-integrin/FAK signaling, cancer cell invasion and metastasis through CRKL.Sci Rep. 2016 Jan 5;6:18652. doi: 10.1038/srep18652.
• [17] CRKL protein overexpression enhances cell proliferation and invasion in pancreatic cancer.Tumour Biol. 2015 Feb;36(2):1015-22. doi: 10.1007/s13277-014-2706-2. Epub 2014 Oct 16.
• [18] Interaction between AR signalling and CRKL bypasses casodex inhibition in prostate cancer.Cell Signal. 2010 Dec;22(12):1874-81. doi: 10.1016/j.cellsig.2010.07.015. Epub 2010 Aug 2.
• [19] Delineation of a recognizable phenotype for the recurrent LCR22-C to D/E atypical 22q11.2 deletion.Am J Med Genet A. 2016 Jun;170(6):1485-94. doi: 10.1002/ajmg.a.37614. Epub 2016 Mar 17.
• [20] Recurrent amplification in the 22q11 region in laryngeal squamous cell carcinoma results in overexpression of the CRKL but not the MAPK1 oncogene.Cancer Biomark. 2010-2011;8(1):11-9. doi: 10.3233/DMA-2011-0814.
• [21] Expression of signaling adaptor proteins predicts poor prognosis in pancreatic ductal adenocarcinoma.Diagn Pathol. 2017 May 30;12(1):42. doi: 10.1186/s13000-017-0633-4.
• [22] The clinical implications of Crk-like adaptor protein expression in papillary thyroid microcarcinoma.Tumour Biol. 2014 Dec;35(12):12435-40. doi: 10.1007/s13277-014-2561-1. Epub 2014 Sep 4.
• [23] From desk to bed: computational simulations provide indication for rheumatoid arthritis clinical trials.BMC Syst Biol. 2013 Jan 22;7:10. doi: 10.1186/1752-0509-7-10.
• [24] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [25] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [28] Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells. Clin Cancer Res. 2006 Oct 1;12(19):5869-78. doi: 10.1158/1078-0432.CCR-06-0980.
• [29] Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. Cancer Res. 2009 May 1;69(9):3927-36. doi: 10.1158/0008-5472.CAN-08-2978. Epub 2009 Apr 14.
• [30] Establishment and characterization of a novel imatinib-sensitive chronic myeloid leukemia cell line MYL, and an imatinib-resistant subline MYL-R showing overexpression of Lyn. Eur J Haematol. 2007 May;78(5):417-31. doi: 10.1111/j.1600-0609.2007.00835.x.
• [31] Endoplasmic reticulum stress-mediated apoptosis in imatinib-resistant leukemic K562-r cells triggered by AMN107 combined with arsenic trioxide. Exp Biol Med (Maywood). 2013 Aug 1;238(8):932-42. doi: 10.1177/1535370213492689. Epub 2013 Jul 24.
• [32] Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells. Oncotarget. 2015 Aug 21;6(24):20231-40. doi: 10.18632/oncotarget.4047.
• [33] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [34] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [35] A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity. Toxicol Sci. 2015 Jan;143(1):147-55. doi: 10.1093/toxsci/kfu215. Epub 2014 Oct 10.
• [36] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [37] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [38] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [39] [Mechanism of cinnamic aldehyde-inducing apoptosis of chronic myeloid leukemic cells in vitro]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Jun;19(3):617-20.