Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMZKPI8)

• Drug Name: TAK-715 Drug Info
• Synonyms: P38 MAP kinase inhibitor (rheumatoid arthritis), Takeda

Indication

Disease Entry	ICD 11	Status	REF
Rheumatoid arthritis	FA20	Phase 2	[1]

• Cross-matching ID:
  PubChem CID: 9952773
  ChEBI ID: CHEBI:91360
  CAS Number: CAS 303162-79-0
  TTD Drug ID: DMZKPI8

Molecule-Related Drug Atlas

Drug(s) Targeting Stress-activated protein kinase (p38)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-07265803	DM3E6Q4	Dilated cardiomyopathy	BC43.0	Phase 3	[4]
ARRY-797	DMJ48AB	Dilated cardiomyopathy	BC43.0	Phase 2	[5]
BMS-582949	DMGYXFP	Atherosclerosis	BD40	Phase 2	[6]
AZD7624	DMEW3K9	Chronic obstructive pulmonary disease	CA22	Phase 2	[7]
GSK2269557	DMIN0SV	Asthma	CA23	Phase 2	[8]
MW150	DMBRVXB	Alzheimer disease	8A20	Phase 2	[9]
LY-2228820	DMHXTNW	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[10]
PUR1800	DM6H10N	Chronic obstructive pulmonary disease	CA22	Phase 1	[11]
ARRY-614	DMXD93K	Arthritis	FA20	Discontinued in Phase 1	[12]
TA-5493	DMFES2K	Inflammation	1A00-CA43.1	Discontinued in Phase 1	[13]

Drug(s) Affected By Forkhead box protein O3 (FOXO3)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fulvestrant	DM0YZC6	Breast cancer	2C60-2C65	Approved	[14]
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[15]
Quercetin	DM3NC4M	Obesity	5B81	Approved	[16]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[17]
Remdesivir	DMBFZ6L	Coronavirus Disease 2019 (COVID-19)	1D6Y	Approved	[18]
Acetic Acid, Glacial	DM4SJ5Y	infection in the ear canal	AA0Y	Approved	[19]
Nefazodone	DM4ZS8M	Major depressive disorder	6A70.3	Approved	[20]
Arsenic trioxide	DM61TA4	Acute lymphoblastic leukaemia	2A85	Approved	[21]
Leflunomide	DMR8ONJ	Arthritis	FA20	Approved	[22]
Ciclosporin	DMAZJFX	Graft-versus-host disease	4B24	Approved	[23]

Drug(s) Affected By NAD-dependent protein deacylase sirtuin-6 (SIRT6)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[24]
Testosterone	DM7HUNW	Hot flushes	GA30	Approved	[25]
Hesperetin	DMKER83	High blood cholesterol level	5C80.00	Approved	[26]
Paclitaxel	DMLB81S	Breast carcinoma		Approved	[27]
Cupric Sulfate	DMP0NFQ	Fungal infection	1F29-1F2F	Approved	[28]
Resveratrol	DM3RWXL	Giant cell arteritis	4A44.2	Phase 3	[29]
SEN-196	DMLDBQ5	Huntington disease	8A01.10	Phase 2	[30]
TAK-243	DM4GKV2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[31]
NORCANTHARIDIN	DM9B6Y1	Discovery agent	N.A.	Investigative	[27]
paraquat	DMR8O3X	Discovery agent	N.A.	Investigative	[32]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Stress-activated protein kinase (p38)	TTWELHI	NOUNIPROTAC	Inhibitor	[2]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Gene/Protein Processing	[3]
NAD-dependent protein deacylase sirtuin-6 (SIRT6)	OTF755ZO	SIR6_HUMAN	Gene/Protein Processing	[3]

References

• [1] ClinicalTrials.gov (NCT00760864) Safety and Efficacy of TAK-715 in Subjects With Rheumatoid Arthritis. U.S. National Institutes of Health.
• [2] Inhibition of Wnt/beta-catenin signaling by p38 MAP kinase inhibitors is explained by cross-reactivity with casein kinase Idelta/ . Chem Biol. 2011 Apr 22;18(4):485-94.
• [3] Oleanolic acid induces HCT116 colon cancer cell death through the p38/FOXO3a/Sirt6 pathway. Chem Biol Interact. 2022 Aug 25;363:110010. doi: 10.1016/j.cbi.2022.110010. Epub 2022 Jun 9.
• [4] Clinical pipeline report, company report or official report of Pfizer
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38alpha inhibitor. Bioorg Med Chem Lett. 2013 May 15;23(10):3028-33.
• [7] Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2015 Mar;24(3):383-92.
• [8] Evaluation of WO2012032067 and WO2012055846: two selective PI3Kdelta inhibitors, which is GSK-2269557. Expert Opin Ther Pat. 2012 Aug;22(8):965-70.
• [9] p38alpha MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10245-E10254.
• [10] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7959).
• [11] Clinical pipeline report, company report or official report of Pulmatrix Lexington, MA
• [12] Cmpany report (Arraybiopharma)
• [13] US patent application no. 2008,0269,123, Methods for treating polycystic kidney disease (pkd) or other cyst forming diseases.
• [14] Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER. BMC Cancer. 2015 Oct 15;15:702. doi: 10.1186/s12885-015-1699-6.
• [15] Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. Mol Endocrinol. 2006 Oct;20(10):2444-55. doi: 10.1210/me.2006-0118. Epub 2006 May 18.
• [16] Quercetin and Its Fermented Extract as a Potential Inhibitor of Bisphenol A-Exposed HT-29 Colon Cancer Cells' Viability. Int J Mol Sci. 2023 Mar 15;24(6):5604. doi: 10.3390/ijms24065604.
• [17] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [18] An in vitro study on anti-carcinogenic effect of remdesivir in human ovarian cancer cells via generation of reactive oxygen species. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221089257. doi: 10.1177/09603271221089257.
• [19] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [20] Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity. Food Chem Toxicol. 2016 Aug;94:148-58. doi: 10.1016/j.fct.2016.06.001. Epub 2016 Jun 8.
• [21] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [24] Sirt6 mediates antioxidative functions by increasing Nrf2 abundance. Exp Cell Res. 2023 Jan 1;422(1):113409. doi: 10.1016/j.yexcr.2022.113409. Epub 2022 Nov 7.
• [25] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [26] Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact. 2019 Aug 1;308:269-278.
• [27] Norcantharidin combined with paclitaxel induces endoplasmic reticulum stress mediated apoptotic effect in prostate cancer cells by targeting SIRT7 expression. Environ Toxicol. 2021 Nov;36(11):2206-2216. doi: 10.1002/tox.23334. Epub 2021 Jul 16.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature. 2015 Mar 19;519(7543):370-3. doi: 10.1038/nature14028. Epub 2014 Dec 22.
• [30] Sirtuins are Unaffected by PARP Inhibitors Containing Planar Nicotinamide Bioisosteres. Chem Biol Drug Des. 2016 Mar;87(3):478-82. doi: 10.1111/cbdd.12680. Epub 2015 Nov 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] SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic Acids Res. 2019 Sep 5;47(15):7914-7928. doi: 10.1093/nar/gkz528.