Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTWT68S)

• DOT Name: CASP8-associated protein 2 (CASP8AP2)
• Synonyms: FLICE-associated huge protein
• Gene Name: CASP8AP2
• Related Disease:
  Anxiety
  Anxiety disorder
  Atrial fibrillation
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colorectal neoplasm
  Congestive heart failure
  Coronary heart disease
  Depression
  Neoplasm
  Skin neoplasm
  Small intestine lymphoma
  Trigeminal neuralgia
  Adenocarcinoma
  Carcinoma
  Osteoarthritis
  Peripheral arterial disease
  Acute lymphocytic leukaemia
  Metastatic malignant neoplasm
  Advanced cancer
  Pachyonychia congenita 3
  Temporal lobe epilepsy
  Type-1/2 diabetes
• UniProt ID: C8AP2_HUMAN
• PDB ID: 2LR8; 6ANO; 6AOZ; 6AP0
• Pfam ID: PF21227
• Sequence:
  MAADDDNGDGTSLFDVFSASPLKNNDEGSLDIYAGLDSAVSDSASKSCVPSRNCLDLYEE
  ILTEEGTAKEATYNDLQVEYGKCQLQMKELMKKFKEIQTQNFSLINENQSLKKNISALIK
  TARVEINRKDEEISNLHQRLSEFPHFRNNHKTARTFDTVKTKDLKSRSPHLDDCSKTDHR
  AKSDVSKDVHHSTSLPNLEKEGKPHSDKRSTSHLPTSVEKHCTNGVWSRSHYQVGEGSSN
  EDSRRGRKDIRHSQFNRGTERVRKDLSTGCGDGEPRILEASQRLQGHPEKYGKGEPKTES
  KSSKFKSNSDSDYKGERINSSWEKETPGERSHSRVDSQSDKKLERQSERSQNINRKEVKS
  QDKEERKVDQKPKSVVKDQDHWRRSERASLPHSKNEITFSHNSSKYHLEERRGWEDCKRD
  KSVNSHSFQDGRCPSSLSNSRTHKNIDSKEVDAMHQWENTPLKAERHRTEDKRKREQESK
  EENRHIRNEKRVPTEHLQKTNKETKKTTTDLKKQNEPKTDKGEVLDNGVSEGADNKELAM
  KAESGPNETKNKDLKLSFMKKLNLTLSPAKKQPVSQDNQHKITDIPKSSGVCDSESSMQV
  KTVAYVPSISEHILGEAAVSEHTMGETKSTLLEPKVALLAVTEPRIGISETNKEDENSLL
  VRSVDNTMHCEEPICGTETSFPSPMEIQQTESLFPSTGMKQTINNGRAAAPVVMDVLQTD
  VSQNFGLELDTKRNDNSDYCGISEGMEMKVALSTTVSETTESILQPSIEEADILPIMLSE
  DNNPKFEPSVIVTPLVESKSCHLEPCLPKETLDSSLQQTELMDHRMATGETNSVYHDDDN
  SVLSIDLNHLRPIPEAISPLNSPVRPVAKVLRNESPPQVPVYNNSHKDVFLPNSAHSTSK
  SQSDLNKENQKPIYKSDKCTEADTCKNSPLDELEEGEIRSDSETSKPQESFEKNSKRRVS
  ADVRKSKTIPRRGKSTVCLDKDSRKTHVRIHQTNNKWNKRPDKSSRSSKTEKKDKVMSTS
  SLEKIVPIIAVPSSEQEIMHMLRMIRKHVRKNYMKFKAKFSLIQFHRIIESAILSFTSLI
  KHLNLHKISKSVTTLQKNLCDIIESKLKQVKKNGIVDRLFEQQLPDMKKKLWKFVDDQLD
  YLFAKLKKILVCDSKSFGRDSDEGKLEKTSKQNAQYSNSQKRSVDNSNRELLKEKLSKSE
  DPVHYKSLVGCKKSEENYQDQNNSSINTVKHDIKKNFNICFDNIKNSQSEERSLEVHCPS
  TPKSEKNEGSSIEDAQTSQHATLKPERSFEILTEQQASSLTFNLVSDAQMGEIFKSLLQG
  SDLLDSSVNCTEKSEWELKTPEKQLLETLKCESIPACTTEELVSGVASPCPKMISDDNWS
  LLSSEKGPSLSSGLSLPVHPDVLDESCMFEVSTNLPLSKDNVCSVEKSKPCVSSILLEDL
  AVSLTVPSPLKSDGHLSFLKPDMSSSSTPEEVISAHFSEDALLEEEDASEQDIHLALESD
  NSSSKSSCSSSWTSRSVAPGFQYHPNLPMHAVIMEKSNDHFIVKIRRATPSTSSGLKQSM
  MPDELLTSLPRHGKEADEGPEKEYISCQNTVFKSVEELENSNKNVDGSKSTHEEQSSMIQ
  TQVPDIYEFLKDASDKMGHSDEVADECFKLHQVWETKVPESIEELPSMEEISHSVGEHLP
  NTYVDLTKDPVTETKNLGEFIEVTVLHIDQLGCSGGNLNQSAQILDNSLQADTVGAFIDL
  TQDASSEAKSEGNHPALAVEDLGCGVIQVDEDNCKEEKAQVANRPLKCIVEETYIDLTTE
  SPSSCEVKKDELKSEPGSNCDNSELPGTLHNSHKKRRNISDLNHPHKKQRKETDLTNKEK
  TKKPTQDSCENTEAHQKKASKKKAPPVTKDPSSLKATPGIKDSSAALATSTSLSAKNVIK
  KKGEIIILWTRNDDREILLECQKRGPSFKTFAYLAAKLDKNPNQVSERFQQLMKLFEKSK
  CR
• Function: Participates in TNF-alpha-induced blockade of glucocorticoid receptor (GR) transactivation at the nuclear receptor coactivator level, upstream and independently of NF-kappa-B. Suppresses both NCOA2- and NCOA3-induced enhancement of GR transactivation. Involved in TNF-alpha-induced activation of NF-kappa-B via a TRAF2-dependent pathway. Acts as a downstream mediator for CASP8-induced activation of NF-kappa-B. Required for the activation of CASP8 in FAS-mediated apoptosis. Required for histone gene transcription and progression through S phase.
• Reactome Pathway: SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Strong	Biomarker	[1]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[7]
Depression	DIS3XJ69	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Skin neoplasm	DIS16DDV	Strong	Genetic Variation	[9]
Small intestine lymphoma	DISDOS6S	Strong	Genetic Variation	[10]
Trigeminal neuralgia	DIS31ZY6	Strong	Biomarker	[11]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[12]
Carcinoma	DISH9F1N	moderate	Genetic Variation	[12]
Osteoarthritis	DIS05URM	moderate	Genetic Variation	[13]
Peripheral arterial disease	DIS78WFB	moderate	Biomarker	[14]
Acute lymphocytic leukaemia	DISPX75S	Disputed	Genetic Variation	[15]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[16]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Pachyonychia congenita 3	DISZLC6C	Limited	Biomarker	[17]
Temporal lobe epilepsy	DISNOPXX	Limited	Genetic Variation	[18]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	CASP8-associated protein 2 (CASP8AP2) increases the response to substance of Methotrexate.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of CASP8-associated protein 2 (CASP8AP2).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CASP8-associated protein 2 (CASP8AP2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CASP8-associated protein 2 (CASP8AP2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CASP8-associated protein 2 (CASP8AP2).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of CASP8-associated protein 2 (CASP8AP2).	[24]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of CASP8-associated protein 2 (CASP8AP2).	[25]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol affects the expression of CASP8-associated protein 2 (CASP8AP2).	[26]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of CASP8-associated protein 2 (CASP8AP2).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of CASP8-associated protein 2 (CASP8AP2).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CASP8-associated protein 2 (CASP8AP2).	[33]

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 CASP8-associated protein 2 (CASP8AP2).	[29]

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 affects the methylation of CASP8-associated protein 2 (CASP8AP2).	[30]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of CASP8-associated protein 2 (CASP8AP2).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of CASP8-associated protein 2 (CASP8AP2).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of CASP8-associated protein 2 (CASP8AP2).	[32]

References

• [1] Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.Proc Natl Acad Sci U S A. 2019 May 28;116(22):10943-10951. doi: 10.1073/pnas.1901777116. Epub 2019 May 16.
• [2] Prediction of electro-anatomical substrate and arrhythmia recurrences using APPLE, DR-FLASH and MB-LATER scores in patients with atrial fibrillation undergoing catheter ablation.Sci Rep. 2018 Aug 23;8(1):12686. doi: 10.1038/s41598-018-31133-x.
• [3] Transcription factor E2F3a regulates CASP8AP2 transcription and enhances sensitivity to chemotherapeutic drugs in acute lymphoblastic leukemia.Cancer Cell Int. 2018 Mar 20;18:40. doi: 10.1186/s12935-018-0531-1. eCollection 2018.
• [4] Regional Bias of Intratumoral Genetic Heterogeneity of Apoptosis-Related Genes BAX, APAF1, and FLASH in Colon Cancers with High Microsatellite Instability.Dig Dis Sci. 2015 Jun;60(6):1674-9. doi: 10.1007/s10620-014-3499-2. Epub 2015 Jan 20.
• [5] Mutational analysis of FLASH and PTPN13 genes in colorectal carcinomas.Pathology. 2008 Jan;40(1):31-4. doi: 10.1080/00313020701716441.
• [6] The analysis of left atrial function predicts the severity of functional impairment in chronic heart failure: The FLASH multicenter study.Int J Cardiol. 2019 Jul 1;286:87-91. doi: 10.1016/j.ijcard.2019.03.063. Epub 2019 Mar 29.
• [7] Whole Left Ventricular Coverage Versus Conventional 3-Slice Myocardial Perfusion Magnetic Resonance Imaging for the Detection of Suspected Coronary Artery Disease.Acad Radiol. 2019 Apr;26(4):519-525. doi: 10.1016/j.acra.2018.05.008. Epub 2018 Jun 7.
• [8] An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses.Radiother Oncol. 2019 Oct;139:23-27. doi: 10.1016/j.radonc.2019.03.028. Epub 2019 Apr 19.
• [9] Treatment of a first patient with FLASH-radiotherapy.Radiother Oncol. 2019 Oct;139:18-22. doi: 10.1016/j.radonc.2019.06.019. Epub 2019 Jul 11.
• [10] Development and internal validation of a risk scoring system for gastrointestinal events requiring surgery in gastrointestinal lymphoma patients.J Gastroenterol Hepatol. 2019 Apr;34(4):693-699. doi: 10.1111/jgh.14452. Epub 2018 Sep 19.
• [11] Preoperative evaluation of neurovascular relationship in trigeminal neuralgia by three-dimensional fast low angle shot (3D-FLASH) and three-dimensional constructive interference in steady-state (3D-CISS) MRI sequence.Br J Radiol. 2018 May;91(1085):20170557. doi: 10.1259/bjr.20170557. Epub 2018 Feb 13.
• [12] Immunohistochemical and mutational analysis of FLASH in gastric carcinomas.APMIS. 2007 Aug;115(8):900-5. doi: 10.1111/j.1600-0463.2007.apm_706.x.
• [13] The association between the Mediterranean diet and magnetic resonance parameters for knee osteoarthritis: data from the Osteoarthritis Initiative.Clin Rheumatol. 2018 Aug;37(8):2187-2193. doi: 10.1007/s10067-018-4075-5. Epub 2018 Apr 3.
• [14] Free-Breathing Fast Low-Angle Shot Quiescent-Interval Slice-Selective Magnetic Resonance Angiography for Improved Detection of Vascular Stenoses in the Pelvis and Abdomen: Technical Development.Invest Radiol. 2019 Dec;54(12):752-756. doi: 10.1097/RLI.0000000000000592.
• [15] Low miR-210 and CASP8AP2 expression is associated with a poor outcome in pediatric acute lymphoblastic leukemia.Oncol Lett. 2017 Dec;14(6):8072-8077. doi: 10.3892/ol.2017.7229. Epub 2017 Oct 20.
• [16] Evaluation of Gadopiclenol and P846, 2 High-Relaxivity Macrocyclic Magnetic Resonance Contrast Agents Without Protein Binding, in a Rodent Model of Hepatic Metastases: Potential Solutions for Improved Enhancement at Ultrahigh Field Strength.Invest Radiol. 2019 Sep;54(9):549-558. doi: 10.1097/RLI.0000000000000572.
• [17] Optimization of ZD2 Peptide Targeted Gd(HP-DO3A) for Detection and Risk-Stratification of Prostate Cancer with MRI.ACS Med Chem Lett. 2018 Jun 6;9(7):730-735. doi: 10.1021/acsmedchemlett.8b00172. eCollection 2018 Jul 12.
• [18] Brain morphometric comparison of first-episode schizophrenia and temporal lobe epilepsy.Br J Psychiatry. 1997 Jun;170:515-9. doi: 10.1192/bjp.170.6.515.
• [19] Makes FLASH the difference between the intervention group and the treatment-as-usual group in an evaluation study of a structured education and treatment programme for flash glucose monitoring devices in people with diabetes on intensive insulin therapy: study protocol for a randomised controlled trial.Trials. 2018 Feb 5;19(1):91. doi: 10.1186/s13063-018-2479-9.
• [20] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [21] 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.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [26] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [27] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [28] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [29] 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.
• [30] 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.
• [31] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [32] 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.
• [33] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [34] Differential gene expression profiles may differentiate responder and nonresponder patients with rheumatoid arthritis for methotrexate (MTX) monotherapy and MTX plus tumor necrosis factor inhibitor combined therapy. J Rheumatol. 2012 Aug;39(8):1524-32. doi: 10.3899/jrheum.120092. Epub 2012 Jul 1.