Details of the Drug Combination

General Information of Drug Combination (ID: DC2KT08)

• Drug Combination Name: Celecoxib + Exemestane
• Indication: Metastatic Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Celecoxib (DM6LOQU): Small molecular drug
  Exemestane (DM9HPW3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Celecoxib

Disease Entry	ICD 11	Status	REF
Dysmenorrhea	GA34.3	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Osteoarthritis	FA00-FA05	Approved	[2]
Rheumatoid arthritis	FA20	Approved	[3]
Pain	MG30-MG3Z	Phase 3	[3]
Colon cancer	2B90.Z	Investigative	[2]
Familial adenomatous polyposis	2B90.Y	Investigative	[2]
Precancerous condition	N.A.	Investigative	[2]

Celecoxib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 2 (COX-2)	TTVKILB	PGH2_HUMAN	Inhibitor	[6]

Celecoxib Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]

Indication(s) of Exemestane

Disease Entry	ICD 11	Status	REF
Hormonally-responsive breast cancer	2C60-2C65	Approved	[4]
Male breast carcinoma	N.A.	Investigative	[5]

Exemestane Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[12]

Exemestane Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]

Exemestane Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[14]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[15]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Increases Expression	[15]
Myb-related protein B (MYBL2)	OTZ3JX8Q	MYBB_HUMAN	Increases Expression	[16]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Localization	[17]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[18]
Amphiregulin (AREG)	OTJFOR67	AREG_HUMAN	Increases Expression	[15]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Increases Expression	[16]
Homeobox protein Hox-D11 (HOXD11)	OT9XGA4G	HXD11_HUMAN	Increases Expression	[16]
Pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1)	OTNBHULA	PACR_HUMAN	Increases Expression	[16]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[19]
Kallikrein-7 (KLK7)	OTIWGMO2	KLK7_HUMAN	Increases Expression	[16]
Disabled homolog 2 (DAB2)	OTRMQTMZ	DAB2_HUMAN	Increases Expression	[16]
CD83 antigen (CD83)	OT1V4WQF	CD83_HUMAN	Increases Expression	[16]
Unconventional myosin-IXb (MYO9B)	OTQ94R5K	MYO9B_HUMAN	Increases Expression	[16]
RRP12-like protein (RRP12)	OTQQAEH4	RRP12_HUMAN	Increases Expression	[16]
Dynein axonemal assembly factor 9 (DNAAF9)	OTTKWWQU	DAAF9_HUMAN	Increases Expression	[16]
E3 ubiquitin-protein ligase RNF123 (RNF123)	OTL59S8J	RN123_HUMAN	Increases Expression	[16]
Osteopetrosis-associated transmembrane protein 1 (OSTM1)	OTKNJDH7	OSTM1_HUMAN	Increases Expression	[16]
Glypican-2 (GPC2)	OT3WSQE1	GPC2_HUMAN	Increases Expression	[16]
Tumor necrosis factor receptor superfamily member 14 (TNFRSF14)	OTB82PFO	TNR14_HUMAN	Increases Expression	[16]
Integrator complex subunit 4 (INTS4)	OT5JQ913	INT4_HUMAN	Increases Expression	[16]
Inositol polyphosphate 5-phosphatase K (INPP5K)	OTQFLQKA	INP5K_HUMAN	Increases Expression	[16]
ATP-binding cassette sub-family G member 4 (ABCG4)	OT2XJIOG	ABCG4_HUMAN	Increases Expression	[16]
TRIO and F-actin-binding protein (TRIOBP)	OTGB5WHC	TARA_HUMAN	Increases Expression	[16]
TBC1 domain family member 17 (TBC1D17)	OT75ZWLB	TBC17_HUMAN	Increases Expression	[16]
Kinesin-like protein KIF13B (KIF13B)	OTAFS1YV	KI13B_HUMAN	Increases Expression	[16]
Transcription factor COE1 (EBF1)	OTZ61YYH	COE1_HUMAN	Increases Expression	[16]
Meteorin (METRN)	OTI2645G	METRN_HUMAN	Increases Expression	[16]
Solute carrier family 13 member 4 (SLC13A4)	OTP3N8N3	S13A4_HUMAN	Increases Expression	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast Cancer	DC1HUX2	N. A.	Phase 1	[20]

References

• [1] ClinicalTrials.gov (NCT00525096) Exemestane + Celecoxib vs Exemestane + Placebo in Metastatic Breast Cancer
• [2] Celecoxib FDA Label
• [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: 2892).
• [4] 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: 7073).
• [5] Exemestane FDA Label
• [6] Pfizer. Product Development Pipeline. March 31 2009.
• [7] Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. J Pharmacol Exp Ther. 2000 May;293(2):453-9.
• [8] Sulfonation of 17beta-estradiol and inhibition of sulfotransferase activity by polychlorobiphenylols and celecoxib in channel catfish, Ictalurus punctatus. Aquat Toxicol. 2007 Mar 10;81(3):286-92.
• [9] Celecoxib is a substrate of CYP2D6: impact on celecoxib metabolism in individuals with CYP2C9*3 variants. Drug Metab Pharmacokinet. 2018 Oct;33(5):219-227.
• [10] Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics. 2009 Sep;10(9):1489-510.
• [11] Drug interactions in dentistry: the importance of knowing your CYPs. J Am Dent Assoc. 2004 Mar;135(3):298-311.
• [12] Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
• [13] In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17beta-dihydroexemestane. Pharmacol Res Perspect. 2017 Apr 27;5(3):e00314.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [15] Characterization of the weak estrogen receptor alpha agonistic activity of exemestane. Breast Cancer Res Treat. 2009 Aug;116(3):461-70. doi: 10.1007/s10549-008-0151-x. Epub 2008 Aug 3.
• [16] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [17] Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform. Toxicology. 2017 Jun 15;385:48-58. doi: 10.1016/j.tox.2017.05.001. Epub 2017 May 4.
• [18] Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
• [19] Aromatase inhibitors: cellular and molecular effects. J Steroid Biochem Mol Biol. 2005 May;95(1-5):83-9. doi: 10.1016/j.jsbmb.2005.04.010.
• [20] ClinicalTrials.gov (NCT00201773) Exemestane With Celecoxib as Neoadjuvant Treatment in Postmenopausal Women With Stage II, III, and IV Breast Cancer