Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ923OB)

DOT Name	Protein IMPACT (IMPACT)
Synonyms	Imprinted and ancient gene protein homolog
Gene Name	IMPACT
Related Disease	Thyroid gland papillary carcinoma ( ) Acute lymphocytic leukaemia ( ) Advanced cancer ( ) Attention deficit hyperactivity disorder ( ) Bipolar disorder ( ) Breast cancer ( ) Cardiac failure ( ) Childhood acute lymphoblastic leukemia ( ) Colorectal carcinoma ( ) Congestive heart failure ( ) Crohn disease ( ) Gastric cancer ( ) Haemophilia A ( ) Hepatitis C virus infection ( ) High blood pressure ( ) Lung carcinoma ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Psoriatic arthritis ( ) Rheumatoid arthritis ( ) Stomach cancer ( ) Systemic lupus erythematosus ( ) Ulcerative colitis ( ) Chronic obstructive pulmonary disease ( ) Obesity ( ) Sarcoma ( ) Soft tissue sarcoma ( ) Migraine disorder ( ) Prostate cancer ( ) Prostate carcinoma ( ) Thyroid gland undifferentiated (anaplastic) carcinoma ( ) Asthma ( ) Cardiac disease ( ) Cardiovascular disease ( ) Congenital heart disease ( ) Inflammatory bowel disease ( ) Non-insulin dependent diabetes ( ) Post-traumatic stress disorder ( ) Sexually transmitted infection ( ) Stroke ( ) Type-1/2 diabetes ( ) Venous thromboembolism ( )
UniProt ID	IMPCT_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF05773 ; PF01205
Sequence	MAEGDAGSDQRQNEEIEAMAAIYGEEWCVIDDCAKIFCIRISDDIDDPKWTLCLQVMLPN EYPGTAPPIYQLNAPWLKGQERADLSNSLEEIYIQNIGESILYLWVEKIRDVLIQKSQMT EPGPDVKKKTEEEDVECEDDLILACQPESSLKALDFDISETRTEVEVEELPPIDHGIPIT DRRSTFQAHLAPVVCPKQVKMVLSKLYENKKIASATHNIYAYRIYCEDKQTFLQDCEDDG ETAAGGRLLHLMEILNVKNVMVVVSRWYGGILLGPDRFKHINNCARNILVEKNYTNSPEE SSKALGKNKKVRKDKKRNEH
Function	Translational regulator that ensures constant high levels of translation upon a variety of stress conditions, such as amino acid starvation, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation. Plays a role as a negative regulator of the EIF2AK4/GCN2 kinase activity; impairs GCN1-mediated EIF2AK4/GCN2 activation, and hence EIF2AK4/GCN2-mediated eIF-2-alpha phosphorylation and subsequent down-regulation of protein synthesis. May be required to regulate translation in specific neuronal cells under amino acid starvation conditions by preventing GCN2 activation and therefore ATF4 synthesis. Through its inhibitory action on EIF2AK4/GCN2, plays a role in differentiation of neuronal cells by stimulating neurite outgrowth.
Tissue Specificity	Widely expressed. Expressed at high level in brain.
Reactome Pathway	Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012 )

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Haemophilia A	DIS0RQ2E	Strong	Genetic Variation	[11]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Psoriatic arthritis	DISLWTG2	Strong	Genetic Variation	[17]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[18]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[19]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[20]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[21]
Obesity	DIS47Y1K	moderate	Biomarker	[22]
Sarcoma	DISZDG3U	moderate	Biomarker	[23]
Soft tissue sarcoma	DISSN8XB	moderate	Biomarker	[23]
Migraine disorder	DISFCQTG	Disputed	Biomarker	[24]
Prostate cancer	DISF190Y	Disputed	Biomarker	[25]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[25]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Disputed	Genetic Variation	[26]
Asthma	DISW9QNS	Limited	Biomarker	[27]
Cardiac disease	DISVO1I5	Limited	Biomarker	[28]
Cardiovascular disease	DIS2IQDX	Limited	Biomarker	[29]
Congenital heart disease	DISQBA23	Limited	Biomarker	[28]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[30]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[31]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[32]
Sexually transmitted infection	DISIVIAL	Limited	Genetic Variation	[33]
Stroke	DISX6UHX	Limited	Biomarker	[34]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[31]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[35]
------------------------------------------------------------------------------------


⏷ Show the Full List of 42 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

5 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 Protein IMPACT (IMPACT).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein IMPACT (IMPACT).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein IMPACT (IMPACT).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein IMPACT (IMPACT).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein IMPACT (IMPACT).	[42]
------------------------------------------------------------------------------------

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein IMPACT (IMPACT).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein IMPACT (IMPACT).	[41]
------------------------------------------------------------------------------------

References

1	Impact factors for the outcome of the first (131)I radiotherapy in patients with papillary thyroid carcinoma after total thyroidectomy.Ann Nucl Med. 2019 Mar;33(3):177-183. doi: 10.1007/s12149-018-01321-w. Epub 2018 Dec 4.
2	The effect of adopting pediatric protocols in adolescents and young adults with acute lymphoblastic leukemia in pediatric vs adult centers: An IMPACT Cohort study.Cancer Med. 2019 May;8(5):2095-2103. doi: 10.1002/cam4.2096. Epub 2019 Mar 26.
3	Bringing Prostate Cancer Germline Genetics into Clinical Practice.J Urol. 2019 Aug;202(2):223-230. doi: 10.1097/JU.0000000000000137. Epub 2019 Jul 8.
4	Baseline Neurocognitive Performance and Symptoms in Those With Attention Deficit Hyperactivity Disorders and History of Concussion With Previous Loss of Consciousness.Front Neurol. 2019 Apr 24;10:396. doi: 10.3389/fneur.2019.00396. eCollection 2019.
5	Human homolog of the mouse imprinted gene Impact resides at the pericentric region of chromosome 18 within the critical region for bipolar affective disorder.Mol Psychiatry. 2001 Jan;6(1):87-91. doi: 10.1038/sj.mp.4000799.
6	Immunohistochemical analysis of estrogen receptor in breast cancer with ESR1 mutations detected by hybrid capture-based next-generation sequencing.Mod Pathol. 2019 Jan;32(1):81-87. doi: 10.1038/s41379-018-0116-5. Epub 2018 Aug 29.
7	Rationale and design of the IMPACT EU-trial: improve management of heart failure with procalcitonin biomarkers in cardiology (BIC)-18.Biomarkers. 2018 Feb;23(1):97-103. doi: 10.1080/1354750X.2017.1420823. Epub 2018 Jan 8.
8	Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels.J Clin Oncol. 2016 Jun 20;34(18):2141-7. doi: 10.1200/JCO.2015.65.1067. Epub 2016 Mar 28.
9	F-calprotectin and Blood Markers Correlate to Quality of Life in Pediatric Inflammatory Bowel Disease.J Pediatr Gastroenterol Nutr. 2017 Nov;65(5):539-545. doi: 10.1097/MPG.0000000000001540.
10	Impact factors that modulate gastric cancer risk in Helicobacter pylori-infected rodent models.Helicobacter. 2019 Aug;24(4):e12580. doi: 10.1111/hel.12580. Epub 2019 Apr 4.
11	Interrelationship between depression, anxiety, pain, and treatment adherence in hemophilia: results from a US cross-sectional survey.Patient Prefer Adherence. 2019 Sep 20;13:1577-1587. doi: 10.2147/PPA.S212723. eCollection 2019.
12	Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease.J Viral Hepat. 2017 Apr;24(4):287-294. doi: 10.1111/jvh.12645. Epub 2016 Nov 23.
13	Research-grade data in the real world: challenges and opportunities in data quality from a pragmatic trial in community-based practices.J Am Med Inform Assoc. 2019 Aug 1;26(8-9):847-854. doi: 10.1093/jamia/ocz062.
14	Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets.Clin Cancer Res. 2016 Jul 15;22(14):3618-29. doi: 10.1158/1078-0432.CCR-15-2946. Epub 2016 Mar 9.
15	Tumor mutational load predicts survival after immunotherapy across multiple cancer types.Nat Genet. 2019 Feb;51(2):202-206. doi: 10.1038/s41588-018-0312-8. Epub 2019 Jan 14.
16	RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition.Clin Cancer Res. 2018 Mar 15;24(6):1436-1447. doi: 10.1158/1078-0432.CCR-17-2343. Epub 2017 Nov 10.
17	Disease activity states of the DAPSA, a psoriatic arthritis specific instrument, are valid against functional status and structural progression.Ann Rheum Dis. 2017 Feb;76(2):418-421. doi: 10.1136/annrheumdis-2016-209511. Epub 2016 Jul 25.
18	IMPACT: Genomic Annotation of Cell-State-Specific Regulatory Elements Inferred from the Epigenome of Bound Transcription Factors.Am J Hum Genet. 2019 May 2;104(5):879-895. doi: 10.1016/j.ajhg.2019.03.012. Epub 2019 Apr 18.
19	Secular trends in the impact factors of SLE publications over a 45-year period-a systematic review.Lupus. 2018 May;27(6):1018-1022. doi: 10.1177/0961203317751855. Epub 2018 Jan 10.
20	Impact of inflammatory bowel disease on Japanese patients' quality of life: results of a patient questionnaire survey.J Gastroenterol. 2017 May;52(5):555-567. doi: 10.1007/s00535-016-1241-x. Epub 2016 Jul 28.
21	Cost-Effectiveness Of Once-Daily Single-Inhaler Triple Therapy In COPD: The IMPACT Trial.Int J Chron Obstruct Pulmon Dis. 2019 Nov 29;14:2681-2695. doi: 10.2147/COPD.S216072. eCollection 2019.
22	The GCN2 inhibitor IMPACT contributes to diet-induced obesity and body temperature control.PLoS One. 2019 Jun 5;14(6):e0217287. doi: 10.1371/journal.pone.0217287. eCollection 2019.
23	ROS1-GOPC/FIG: a novel gene fusion in hepatic angiosarcoma.Oncotarget. 2019 Jan 4;10(2):245-251. doi: 10.18632/oncotarget.26521. eCollection 2019 Jan 4.
24	Acute Effects of Concussion in Youth With Pre-existing Migraines.Clin J Sport Med. 2021 Sep 1;31(5):430-437. doi: 10.1097/JSM.0000000000000791.
25	Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.Eur Urol. 2019 Dec;76(6):831-842. doi: 10.1016/j.eururo.2019.08.019. Epub 2019 Sep 16.
26	Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers.Clin Cancer Res. 2018 Jul 1;24(13):3059-3068. doi: 10.1158/1078-0432.CCR-18-0373. Epub 2018 Apr 3.
27	The frequency of asthma exacerbations and healthcare utilization in patients with asthma from the UK and USA.BMC Pulm Med. 2017 Apr 27;17(1):74. doi: 10.1186/s12890-017-0409-3.
28	Quality and Safety in Health Care, Part XLI: The IMPACT Registry.Clin Nucl Med. 2018 Nov;43(11):815-817. doi: 10.1097/RLU.0000000000002107.
29	Cost-Effectiveness of the US Food and Drug Administration Added Sugar Labeling Policy for Improving Diet and Health.Circulation. 2019 Jun 4;139(23):2613-2624. doi: 10.1161/CIRCULATIONAHA.118.036751. Epub 2019 Apr 15.
30	Medical staff tend to underestimate the quality of life in children and adolescents with inflammatory bowel disease.Acta Paediatr. 2019 Jan;108(1):138-142. doi: 10.1111/apa.14498. Epub 2018 Aug 7.
31	Development of the influence, motivation, and patient activation in diabetes (IMPACT-D? measure.Diabetes Res Clin Pract. 2020 Jan;159:107965. doi: 10.1016/j.diabres.2019.107965. Epub 2019 Dec 2.
32	Improving treatment for patients with childhood abuse related posttraumatic stress disorder (IMPACT study): protocol for a multicenter randomized trial comparing prolonged exposure with intensified prolonged exposure and phase-based treatment.BMC Psychiatry. 2018 Dec 12;18(1):385. doi: 10.1186/s12888-018-1967-5.
33	Study protocol of the iMPaCT project: a longitudinal cohort study assessing psychological determinants, sexual behaviour and chlamydia (re)infections in heterosexual STI clinic visitors.BMC Infect Dis. 2018 Nov 13;18(1):559. doi: 10.1186/s12879-018-3498-6.
34	Activities and participation after stroke: validity and reliability of the Turkish version of IMPACT-S questionnaire.Disabil Rehabil. 2020 Jun;42(13):1912-1917. doi: 10.1080/09638288.2018.1542038. Epub 2019 Jan 17.
35	Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis.Oncologist. 2013;18(12):1321-9. doi: 10.1634/theoncologist.2013-0226. Epub 2013 Nov 8.
36	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
37	Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
38	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.
39	Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
40	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.
41	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.
42	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.