Details of the Drug Combination

General Information of Drug Combination (ID: DCJFT42)

• Drug Combination Name: Tofacitinib + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Tofacitinib (DMBS370): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 21.67
  Bliss Independence Score: 21.67
  Loewe Additivity Score: 12.64
  LHighest Single Agent (HSA) Score: 12.64

Molecular Interaction Atlas of This Drug Combination

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	[8]

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	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]

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	[7]
C-X-C motif chemokine 11 (CXCL11)	OT353XE3	CXL11_HUMAN	Decreases Expression	[10]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Decreases Expression	[7]
C-X-C motif chemokine 13 (CXCL13)	OT2AT4N8	CXL13_HUMAN	Decreases Expression	[11]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Decreases Activity	[6]
Cytochrome c oxidase subunit 1 (COX1)	OTG3O9BN	COX1_HUMAN	Increases Expression	[7]
2'-5'-oligoadenylate synthase 1 (OAS1)	OT8ZLOCY	OAS1_HUMAN	Decreases Expression	[7]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Decreases Expression	[10]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[11]
Ubiquitin-like protein ISG15 (ISG15)	OT53QQ7N	ISG15_HUMAN	Decreases Expression	[7]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[10]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Increases Expression	[7]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Decreases Expression	[11]
Keratin, type I cytoskeletal 16 (KRT16)	OTGA0EQN	K1C16_HUMAN	Decreases Expression	[12]
Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)	OTXOQDSG	IFIT1_HUMAN	Decreases Expression	[10]
Interferon-induced transmembrane protein 1 (IFITM1)	OTECO1G8	IFM1_HUMAN	Decreases Expression	[7]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[11]
Interferon-induced GTP-binding protein Mx1 (MX1)	OT6X8G5T	MX1_HUMAN	Decreases Expression	[7]
Interferon-induced GTP-binding protein Mx2 (MX2)	OT05NF37	MX2_HUMAN	Decreases Expression	[7]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Decreases Activity	[13]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[6]
2'-5'-oligoadenylate synthase 2 (OAS2)	OT64CCTM	OAS2_HUMAN	Decreases Expression	[7]
Succinate dehydrogenase flavoprotein subunit, mitochondrial (SDHA)	OTOJ8QFF	SDHA_HUMAN	Increases Expression	[7]
Interferon alpha-inducible protein 27, mitochondrial (IFI27)	OTI2XGIT	IFI27_HUMAN	Decreases Expression	[7]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Activity	[14]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Decreases Expression	[10]
Signal transducer and activator of transcription 5A (STAT5A)	OTBSJGN3	STA5A_HUMAN	Decreases Phosphorylation	[15]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Decreases Expression	[7]
Signal transducer and activator of transcription 5B (STAT5B)	OTZVPEBT	STA5B_HUMAN	Decreases Phosphorylation	[15]
Interferon-induced 35 kDa protein (IFI35)	OTV9RZ53	IN35_HUMAN	Decreases Expression	[7]
Interferon regulatory factor 9 (IRF9)	OTK4MYQJ	IRF9_HUMAN	Decreases Expression	[7]
AMP deaminase 2 (AMPD2)	OTBS30JU	AMPD2_HUMAN	Decreases Expression	[16]
C-X-C motif chemokine 9 (CXCL9)	OTMFVZKZ	CXCL9_HUMAN	Decreases Expression	[10]
Bone marrow stromal antigen 2 (BST2)	OTU4LCJV	BST2_HUMAN	Decreases Expression	[7]
Sonic hedgehog protein (SHH)	OTOG2BXF	SHH_HUMAN	Increases Expression	[7]
Secreted frizzled-related protein 5 (SFRP5)	OTLCVVSH	SFRP5_HUMAN	Increases Expression	[7]
Interferon-induced protein 44 (IFI44)	OTOKSZVA	IFI44_HUMAN	Decreases Expression	[7]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Decreases Expression	[7]
Interferon regulatory factor 7 (IRF7)	OTC1A2PQ	IRF7_HUMAN	Decreases Expression	[10]
Kelch-like protein 31 (KLHL31)	OTXZVWDL	KLH31_HUMAN	Increases Expression	[7]
Histone-lysine N-methyltransferase PRDM16 (PRDM16)	OT0BGA27	PRD16_HUMAN	Increases Expression	[7]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Metabolism	[17]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Metabolism	[18]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Metabolism	[17]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[4]
Acute myeloid leukaemia	2A60	Approved	[5]
Adult acute monocytic leukemia	N.A.	Approved	[4]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[20]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[21]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[22]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[22]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[23]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[23]

Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[19]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[24]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[19]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[25]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[26]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[19]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[27]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[19]

References

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• [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] Idarubicin 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: 7083).
• [6] 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.
• [7] 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.
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [9] The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug Metab Dispos. 2014 Apr;42(4):759-73.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Effects of tofacitinib on nucleic acid metabolism in human articular chondrocytes. Mod Rheumatol. 2015 Jul;25(4):522-7. doi: 10.3109/14397595.2014.995874. Epub 2015 Jan 13.
• [17] 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.
• [18] Elucidating the Mechanism of Tofacitinib Oxidative Decyanation. Drug Metab Lett. 2016;10(2):136-43. doi: 10.2174/1872312810666160427104954.
• [19] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [22] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [23] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [24] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
• [25] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [26] The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
• [27] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.