Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMN4XSX)

• DOT Name: CDK5 and ABL1 enzyme substrate 1 (CABLES1)
• Synonyms: Interactor with CDK3 1; Ik3-1
• Gene Name: CABLES1
• Related Disease:
  Adenoma
  Breast carcinoma
  Carney complex
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Cushing disease
  Intestinal neoplasm
  Lung cancer
  Lung carcinoma
  Neoplasm
  Pituitary gland disorder
  Advanced cancer
  Bipolar disorder
  Endometrial carcinoma
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Schizoaffective disorder
  Schizophrenia
  Colorectal neoplasm
  Colonic neoplasm
  Lung adenocarcinoma
  Non-small-cell lung cancer
• UniProt ID: CABL1_HUMAN
• Pfam ID: PF00134
• Sequence:
  MAAAAAAATTAACSSGSAGTDAAGASGLQQPPPQPQPQPAAAAPAQPPPEPPRKPRMDPR
  RRQAALSFLTNISLDGRLPPQDAEWGGGEEGGAAKPGAGGACGARTRFSLLAAAERGGCI
  ALAAPGTPAAGLAAGSGPCLPQPSSLPPLIPGGHATVSGPGVARGFASPLGAGRASGEQW
  QPPRPAPLAACAQLQLLDGSGAAGQEELEEDDAFISVQVPAAAFLGSGTPGSGSGSRGRL
  NSFTQGILPIAFSRPTSQNYCSLEQPGQGGSTSAFEQLQRSRRRLISQRSSLETLEDIEE
  NAPLRRCRTLSGSPRPKNFKKIHFIKNMRQHDTRNGRIVLISGRRSFCSIFSVLPYRDST
  QVGDLKLDGGRQSTGAVSLKEIIGLEGVELGADGKTVSYTQFLLPTNAFGARRNTIDSTS
  SFSQFRNLSHRSLSIGRASGTQGSLDTGSDLGDFMDYDPNLLDDPQWPCGKHKRVLIFPS
  YMTTVIDYVKPSDLKKDMNETFKEKFPHIKLTLSKIRSLKREMRKLAQEDCGLEEPTVAM
  AFVYFEKLALKGKLNKQNRKLCAGACVLLAAKIGSDLKKHEVKHLIDKLEEKFRLNRREL
  IAFEFPVLVALEFALHLPEHEVMPHYRRLVQSS
• Function: Cyclin-dependent kinase binding protein. Enhances cyclin-dependent kinase tyrosine phosphorylation by nonreceptor tyrosine kinases, such as that of CDK5 by activated ABL1, which leads to increased CDK5 activity and is critical for neuronal development, and that of CDK2 by WEE1, which leads to decreased CDK2 activity and growth inhibition. Positively affects neuronal outgrowth. Plays a role as a regulator for p53/p73-induced cell death.
• Tissue Specificity: Expressed in breast, pancreas, colon, head and neck (at protein level). Strongly decreased in more than half of cases of atypical endometrial hyperplasia and in more than 90% of endometrial cancers.
• Reactome Pathway:
  Cyclin A (R-HSA-69656)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Cyclin E associated events during G1/S transition (R-HSA-69202)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Carney complex	DISVL3IP	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[5]
Cushing disease	DISOG6P2	Strong	Biomarker	[3]
Intestinal neoplasm	DISK0GUH	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Pituitary gland disorder	DIS7XB48	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[9]
Endometrial carcinoma	DISXR5CY	moderate	Altered Expression	[10]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[10]
Ovarian cancer	DISZJHAP	moderate	Posttranslational Modification	[10]
Ovarian neoplasm	DISEAFTY	moderate	Altered Expression	[10]
Schizoaffective disorder	DISLBW6B	moderate	Genetic Variation	[9]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[9]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[5]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[11]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[12]

17 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 CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[22]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[27]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of CDK5 and ABL1 enzyme substrate 1 (CABLES1).	[28]

References

• [1] The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease.J Clin Endocrinol Metab. 2016 Feb;101(2):513-22. doi: 10.1210/jc.2015-3324. Epub 2015 Dec 22.
• [2] Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.Nat Genet. 2014 Aug;46(8):886-90. doi: 10.1038/ng.3041. Epub 2014 Jul 20.
• [3] PATHOGENESIS OF CUSHING DISEASE: AN UPDATE ON THE GENETICS OF CORTICOTROPINOMAS.Endocr Pract. 2018 Oct 2;24(10):907-914. doi: 10.4158/EP-2018-0111. Epub 2018 Aug 7.
• [4] Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in Apc(Min) mice.Cancer Biol Ther. 2013 Jul;14(7):672-8. doi: 10.4161/cbt.25089. Epub 2013 May 31.
• [5] The Cables gene on chromosome 18q is silenced by promoter hypermethylation and allelic loss in human colorectal cancer.Am J Pathol. 2007 Nov;171(5):1509-19. doi: 10.2353/ajpath.2007.070331.
• [6] Cables1 complex couples survival signaling to the cell death machinery.Cancer Res. 2015 Jan 1;75(1):147-158. doi: 10.1158/0008-5472.CAN-14-0036. Epub 2014 Oct 31.
• [7] Cables1 Inhibits Proliferation and Induces Senescence by Angiotensin II via a p21-Dependent Pathway in Human Umbilical Vein Endothelial Cells.J Vasc Res. 2017;54(1):13-21. doi: 10.1159/000452409. Epub 2017 Jan 25.
• [8] The Emerging Role of Cables1 in Cancer and Other Diseases.Mol Pharmacol. 2017 Sep;92(3):240-245. doi: 10.1124/mol.116.107730. Epub 2017 Jan 24.
• [9] Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.Transl Psychiatry. 2017 Oct 24;7(10):e1249. doi: 10.1038/tp.2017.210.
• [10] Mechanisms of Cables 1 gene inactivation in human ovarian cancer development.Cancer Biol Ther. 2008 Feb;7(2):180-88. doi: 10.4161/cbt.7.2.5253. Epub 2007 Nov 15.
• [11] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [12] Loss of cables protein expression in human non-small cell lung cancer: a tissue microarray study.Hum Pathol. 2003 Feb;34(2):143-9. doi: 10.1053/hupa.2003.26.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] 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.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [23] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] 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.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [29] 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.
• [30] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.