Details of the Drug Combination

General Information of Drug Combination (ID: DC093EF)

• Drug Combination Name: Ruxolitinib + (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE
• Indication: Myelofibrosis; Status: Phase 2 [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE (DMTPQ84): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[2]
High-risk myelofibrosis	2A20.2	Approved	[3]
Myelofibrosis	2A22	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[3]
Atopic dermatitis	EA80	Phase 1/2	[7]
Vitiligo	ED63.0	Phase 1/2	[7]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[9]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[9]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[10]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[11]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[11]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[12]

Indication(s) of (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[8]

(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor messenger RNA (GCR mRNA)	TTOZRK6	GCR_HUMAN	Agonist	[13]
Corticosteroid 11-beta-dehydrogenase 1 (HSD11B1)	TTN7BL9	DHI1_HUMAN	Inhibitor	[14]
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Inhibitor	[14]

(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[15]

(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]

(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[17]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Decreases Activity	[18]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Affects Binding	[19]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[20]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Expression	[20]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Affects Binding	[21]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[22]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Expression	[20]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Expression	[20]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases Expression	[20]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[20]
Excitatory amino acid transporter 2 (SLC1A2)	OTEP3QGN	EAA2_HUMAN	Increases Expression	[23]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Increases Expression	[24]
Glucose-6-phosphatase 2 (G6PC2)	OTET1IKU	G6PC2_HUMAN	Increases Expression	[25]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[26]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Secretion	[27]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Increases Chemical Synthesis	[28]
Cytochrome P450 11B1, mitochondrial (CYP11B1)	OTKKL894	C11B1_HUMAN	Increases Chemical Synthesis	[29]

References

• [1] ClinicalTrials.gov (NCT04218071) Actuate 1901: 9-ING-41 in Myelofibrosis. U.S. National Institutes of Health.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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: 2869).
• [9] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
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• [21] Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell. 2005 Aug 5;19(3):367-80. doi: 10.1016/j.molcel.2005.06.026.
• [22] Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect. 2011 Aug;119(8):1142-8. doi: 10.1289/ehp.1002952. Epub 2011 May 4.
• [23] Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem. 2007 Jan 19;282(3):1727-37. doi: 10.1074/jbc.M609822200. Epub 2006 Nov 30.
• [24] Evaluation of an imaging-based in vitro screening platform for estrogenic activity with OECD reference chemicals. Toxicol In Vitro. 2022 Jun;81:105348. doi: 10.1016/j.tiv.2022.105348. Epub 2022 Mar 18.
• [25] G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress. Endocrinology. 2016 Aug;157(8):3002-8. doi: 10.1210/en.2016-1245. Epub 2016 Jun 14.
• [26] Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 2005 Jan;312(1):144-52. doi: 10.1124/jpet.104.073916. Epub 2004 Sep 13.
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• [28] Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives. J Med Chem. 2011 Apr 14;54(7):2307-19.
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