General Information of Drug Combination (ID: DC8XX7S)

Drug Combination Name
Tofacitinib Hydroxychloroquine
Indication
Disease Entry Status REF
Pneumonitis, Interstitial Phase 2 [1]
Component Drugs Tofacitinib   DMBS370 Hydroxychloroquine   DMSIVND
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Tofacitinib
Disease Entry ICD 11 Status REF
Rheumatoid arthritis FA20 Approved [2]
Coronavirus Disease 2019 (COVID-19) 1D6Y Phase 2 [3]
Tofacitinib Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Janus kinase 3 (JAK-3) TTT7PJU JAK3_HUMAN Modulator [9]
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Tofacitinib Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [10]
Mephenytoin 4-hydroxylase (CYP2C19) DEGTFWK CP2CJ_HUMAN Metabolism [10]
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Tofacitinib Interacts with 44 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Suppressor of cytokine signaling 3 (SOCS3) OTY183WJ SOCS3_HUMAN Decreases Expression [8]
C-X-C motif chemokine 11 (CXCL11) OT353XE3 CXL11_HUMAN Decreases Expression [11]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) OTPGHZB9 IFIT3_HUMAN Decreases Expression [8]
C-X-C motif chemokine 13 (CXCL13) OT2AT4N8 CXL13_HUMAN Decreases Expression [12]
Tyrosine-protein kinase JAK2 (JAK2) OTBIDOOR JAK2_HUMAN Decreases Activity [7]
Cytochrome c oxidase subunit 1 (COX1) OTG3O9BN COX1_HUMAN Increases Expression [8]
2'-5'-oligoadenylate synthase 1 (OAS1) OT8ZLOCY OAS1_HUMAN Decreases Expression [8]
C-X-C motif chemokine 10 (CXCL10) OTTLQ6S0 CXL10_HUMAN Decreases Expression [11]
Interstitial collagenase (MMP1) OTI4I2V1 MMP1_HUMAN Decreases Expression [12]
Ubiquitin-like protein ISG15 (ISG15) OT53QQ7N ISG15_HUMAN Decreases Expression [8]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Decreases Expression [11]
Zinc finger protein GLI1 (GLI1) OT1BTAJO GLI1_HUMAN Increases Expression [8]
Stromelysin-1 (MMP3) OTGBI74Z MMP3_HUMAN Decreases Expression [12]
Keratin, type I cytoskeletal 16 (KRT16) OTGA0EQN K1C16_HUMAN Decreases Expression [13]
Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) OTXOQDSG IFIT1_HUMAN Decreases Expression [11]
Interferon-induced transmembrane protein 1 (IFITM1) OTECO1G8 IFM1_HUMAN Decreases Expression [8]
C-C motif chemokine 2 (CCL2) OTAD2HEL CCL2_HUMAN Decreases Expression [12]
Interferon-induced GTP-binding protein Mx1 (MX1) OT6X8G5T MX1_HUMAN Decreases Expression [8]
Interferon-induced GTP-binding protein Mx2 (MX2) OT05NF37 MX2_HUMAN Decreases Expression [8]
Tyrosine-protein kinase JAK1 (JAK1) OT0X3D17 JAK1_HUMAN Decreases Activity [14]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Increases Expression [7]
2'-5'-oligoadenylate synthase 2 (OAS2) OT64CCTM OAS2_HUMAN Decreases Expression [8]
Succinate dehydrogenase flavoprotein subunit, mitochondrial (SDHA) OTOJ8QFF SDHA_HUMAN Increases Expression [8]
Interferon alpha-inducible protein 27, mitochondrial (IFI27) OTI2XGIT IFI27_HUMAN Decreases Expression [8]
Signal transducer and activator of transcription 3 (STAT3) OTAAGKYZ STAT3_HUMAN Decreases Activity [15]
Signal transducer and activator of transcription 1-alpha/beta (STAT1) OTLMBUZ6 STAT1_HUMAN Decreases Expression [11]
Signal transducer and activator of transcription 5A (STAT5A) OTBSJGN3 STA5A_HUMAN Decreases Phosphorylation [16]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10) OT4PXBTA TNF10_HUMAN Decreases Expression [8]
Signal transducer and activator of transcription 5B (STAT5B) OTZVPEBT STA5B_HUMAN Decreases Phosphorylation [16]
Interferon-induced 35 kDa protein (IFI35) OTV9RZ53 IN35_HUMAN Decreases Expression [8]
Interferon regulatory factor 9 (IRF9) OTK4MYQJ IRF9_HUMAN Decreases Expression [8]
AMP deaminase 2 (AMPD2) OTBS30JU AMPD2_HUMAN Decreases Expression [17]
C-X-C motif chemokine 9 (CXCL9) OTMFVZKZ CXCL9_HUMAN Decreases Expression [11]
Bone marrow stromal antigen 2 (BST2) OTU4LCJV BST2_HUMAN Decreases Expression [8]
Sonic hedgehog protein (SHH) OTOG2BXF SHH_HUMAN Increases Expression [8]
Secreted frizzled-related protein 5 (SFRP5) OTLCVVSH SFRP5_HUMAN Increases Expression [8]
Interferon-induced protein 44 (IFI44) OTOKSZVA IFI44_HUMAN Decreases Expression [8]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2) OTCA9WCM RSAD2_HUMAN Decreases Expression [8]
Interferon regulatory factor 7 (IRF7) OTC1A2PQ IRF7_HUMAN Decreases Expression [11]
Kelch-like protein 31 (KLHL31) OTXZVWDL KLH31_HUMAN Increases Expression [8]
Histone-lysine N-methyltransferase PRDM16 (PRDM16) OT0BGA27 PRD16_HUMAN Increases Expression [8]
Cytochrome P450 1A2 (CYP1A2) OTLLBX48 CP1A2_HUMAN Increases Metabolism [18]
Aldo-keto reductase family 1 member C1 (AKR1C1) OTQKR4CM AK1C1_HUMAN Increases Metabolism [19]
Cytochrome P450 2D6 (CYP2D6) OTZJC802 CP2D6_HUMAN Increases Metabolism [18]
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⏷ Show the Full List of 44 DOT(s)
Indication(s) of Hydroxychloroquine
Disease Entry ICD 11 Status REF
Chronic renal failure GB61.Z Approved [4]
Malaria 1F40-1F45 Approved [5]
Plasmodium falciparum malaria 1F40 Approved [4]
Plasmodium malariae malaria N.A. Approved [4]
Plasmodium ovale malaria N.A. Approved [4]
Systemic lupus erythematosus 4A40.0 Approved [4]
Coronavirus Disease 2019 (COVID-19) 1D6Y Phase 3 [6]
Colon cancer 2B90.Z Investigative [4]
Hydroxychloroquine Interacts with 4 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
HUMAN pH-dependent viral fusion/replication (pH-DVF/R) TTD16BI N.A. Inhibitor [20]
HUMAN glycosylation of host receptor (GHR) TTZGK1R N.A. Inhibitor [20]
Toll-like receptor 7 (TLR7) TTRJ1K4 TLR7_HUMAN Antagonist [21]
HUMAN toll-like receptor 7/9 signalling pathway (TLR7/9 pathway) TT3A1EZ N.A. Inhibitor [22]
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Hydroxychloroquine Interacts with 1 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [23]
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Hydroxychloroquine Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [24]
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Hydroxychloroquine Interacts with 30 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 2D6 (CYP2D6) OTZJC802 CP2D6_HUMAN Decreases Activity [25]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) OTPGHZB9 IFIT3_HUMAN Increases Expression [26]
CASP8 and FADD-like apoptosis regulator (CFLAR) OTX14BAS CFLAR_HUMAN Decreases Expression [27]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1) OTY9R6FZ ERN1_HUMAN Increases Expression [26]
Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) OT4TMERS NFAC1_HUMAN Affects Expression [28]
Claudin-1 (CLDN1) OT27KV99 CLD1_HUMAN Increases Expression [29]
Interferon beta (IFNB1) OTYQGUB5 IFNB_HUMAN Increases Expression [26]
C-X-C motif chemokine 10 (CXCL10) OTTLQ6S0 CXL10_HUMAN Increases Expression [26]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) OTRT3F3U HMDH_HUMAN Affects Expression [30]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL) OTG7J4BP PPBT_HUMAN Affects Expression [30]
Transcription factor Jun (JUN) OTCYBO6X JUN_HUMAN Increases Phosphorylation [26]
Cathepsin B (CTSB) OTP9G5QB CATB_HUMAN Affects Localization [31]
72 kDa type IV collagenase (MMP2) OT5NIWA2 MMP2_HUMAN Decreases Expression [32]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases Expression [33]
C-C motif chemokine 2 (CCL2) OTAD2HEL CCL2_HUMAN Increases Expression [33]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Increases Degradation [26]
CD40 ligand (CD40LG) OT75Z6A6 CD40L_HUMAN Decreases Expression [28]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [27]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Increases Expression [26]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Activity [31]
TNF receptor-associated factor 3 (TRAF3) OT5TQBGV TRAF3_HUMAN Increases Expression [26]
Nuclear factor of activated T-cells, cytoplasmic 2 (NFATC2) OTK5T6HZ NFAC2_HUMAN Affects Localization [28]
Sequestosome-1 (SQSTM1) OTGY5D5J SQSTM_HUMAN Increases Expression [34]
Interferon regulatory factor 3 (IRF3) OT81U8ME IRF3_HUMAN Increases Phosphorylation [26]
Occludin (OCLN) OTSUTVWL OCLN_HUMAN Increases Expression [29]
Mitochondrial antiviral-signaling protein (MAVS) OTTQ0J64 MAVS_HUMAN Increases Expression [26]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2) OTCA9WCM RSAD2_HUMAN Increases Expression [26]
Interferon-induced helicase C domain-containing protein 1 (IFIH1) OTZA2AHA IFIH1_HUMAN Increases Expression [26]
Toll-like receptor 9 (TLR9) OTFZ45HX TLR9_HUMAN Decreases Expression [35]
7-dehydrocholesterol reductase (DHCR7) OTLILBUI DHCR7_HUMAN Affects Expression [30]
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⏷ Show the Full List of 30 DOT(s)

References

1 ClinicalTrials.gov (NCT04390061) TOFAcitinib Plus Hydroxycloroquine vs Hydroxycloroquine in Patients With COVID-19 Interstitial Pneumonia
2 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: 5677).
3 ClinicalTrials.gov (NCT04332042) TOFAcitinib in SARS-CoV2 Pneumonia. U.S. National Institutes of Health.
4 Hydroxychloroquine FDA Label
5 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: 7198).
6 ClinicalTrials.gov (NCT04341727) Hydroxychloroquine,Hydroxychloroquine,Azithromycin in the Treatment of SARS CoV-2 Infection (WU352). U.S. National Institutes of Health.
7 Differences in gene expression and alterations in cell cycle of acute myeloid leukemia cell lines after treatment with JAK inhibitors. Eur J Pharmacol. 2015 Oct 15;765:188-97. doi: 10.1016/j.ejphar.2015.08.037. Epub 2015 Aug 20.
8 White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
9 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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11 Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum. 2012 Dec;64(12):3856-66. doi: 10.1002/art.37691.
12 The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015 Jun;74(6):1311-6. doi: 10.1136/annrheumdis-2014-206028. Epub 2014 Nov 14.
13 Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study. J Allergy Clin Immunol. 2016 Apr;137(4):1079-1090. doi: 10.1016/j.jaci.2015.12.1318.
14 JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis. J Immunol Res. 2014;2014:283617. doi: 10.1155/2014/283617. Epub 2014 May 5.
15 EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One. 2012;7(2):e31067. doi: 10.1371/journal.pone.0031067. Epub 2012 Feb 13.
16 Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov. 2012 Jul;2(7):591-7. doi: 10.1158/2159-8290.CD-12-0028. Epub 2012 Jun 15.
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18 Tofacitinib Is a Mechanism-Based Inactivator of Cytochrome P450 3A4. Chem Res Toxicol. 2019 Sep 16;32(9):1791-1800. doi: 10.1021/acs.chemrestox.9b00141. Epub 2019 Aug 26.
19 Elucidating the Mechanism of Tofacitinib Oxidative Decyanation. Drug Metab Lett. 2016;10(2):136-43. doi: 10.2174/1872312810666160427104954.
20 Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
21 TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets. 2007 Dec;6(4):223-35.
22 Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):155-166.
23 MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
24 Hydroxychloroquine: a physiologically-based pharmacokinetic model in the context of cancer-related autophagy modulation. J Pharmacol Exp Ther. 2018 Jun;365(3):447-459.
25 Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M "Influence of hydroxychloroquine on the bioavailability of oral metoprolol." Br J Clin Pharmacol 49 (2000): 549-54. [PMID: 10848718]
26 Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi: 10.1089/jir.2014.0038. Epub 2014 Oct 16.
27 Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes. Clin Exp Immunol. 2006 Jun;144(3):503-11. doi: 10.1111/j.1365-2249.2006.03070.x.
28 Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017 Aug 9;19(1):183. doi: 10.1186/s13075-017-1393-y.
29 Chloroquine and Hydroxychloroquine Increase Retinal Pigment Epithelial Layer Permeability. J Biochem Mol Toxicol. 2015 Jul;29(7):299-304. doi: 10.1002/jbt.21696. Epub 2015 Mar 9.
30 Hydroxychloroquine decreases human MSC-derived osteoblast differentiation and mineralization in vitro. J Cell Mol Med. 2018 Feb;22(2):873-882. doi: 10.1111/jcmm.13373. Epub 2017 Oct 3.
31 Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003 Jun 19;22(25):3927-36. doi: 10.1038/sj.onc.1206622.
32 Attenuation of chloroquine and hydroxychloroquine on the invasive potential of bladder cancer through targeting matrix metalloproteinase 2 expression. Environ Toxicol. 2021 Nov;36(11):2138-2145. doi: 10.1002/tox.23328. Epub 2021 Jul 19.
33 Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia. 2004 Jul;47(1):9-20. doi: 10.1002/glia.20017.
34 d-galactose induces premature senescence of lens epithelial cells by disturbing autophagy flux and mitochondrial functions. Toxicol Lett. 2018 Jun 1;289:99-106. doi: 10.1016/j.toxlet.2018.02.001. Epub 2018 Feb 6.
35 Antagonist-mediated down-regulation of Toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus. Arthritis Res Ther. 2012 Apr 18;14(2):R80. doi: 10.1186/ar3803.