Details of the Drug Combination

General Information of Drug Combination (ID: DC3E1BS)

• Drug Combination Name: Anastrozole + Saracatinib
• Indication: Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Anastrozole (DMNP60F): Small molecular drug
  Saracatinib (DMBLHGP): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Anastrozole

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Estrogen-receptor positive breast cancer	N.A.	Approved	[3]
Obesity	5B81	Approved	[3]

Anastrozole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[7]

Anastrozole Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Putative sodium-coupled neutral amino acid transporter 7 (SLC38A7)	DT2EGUN	S38A7_HUMAN	Substrate	[8]

Anastrozole Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[9]

Anastrozole Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[10]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[11]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[12]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Decreases Activity	[13]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Decreases Expression	[14]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[15]

Indication(s) of Saracatinib

Disease Entry	ICD 11	Status	REF
Hematologic tumour	2B33.Y	Phase 2	[4]
Metastatic colorectal cancer	2B91	Phase 2	[5]
Osteosarcoma	2B51	Phase 2	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[6]

Saracatinib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase ABL1 (ABL)	TT3PJMV	ABL1_HUMAN	Modulator	[16]
Proto-oncogene c-Src (SRC)	TT6PKBN	SRC_HUMAN	Modulator	[16]

Saracatinib Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 7A1 (CYP7A1)	OT8Z5KLD	CP7A1_HUMAN	Increases Expression	[17]
Tyrosine-protein kinase CSK (CSK)	OTP03OD0	CSK_HUMAN	Decreases Activity	[17]
Neural cell adhesion molecule L1 (L1CAM)	OTNWAQ4Y	L1CAM_HUMAN	Decreases Phosphorylation	[18]
Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1)	OTYRXD2T	PMYT1_HUMAN	Decreases Activity	[19]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Oxidation	[20]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Oxidation	[20]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Oxidation	[20]

References

• [1] ClinicalTrials.gov (NCT01216176) A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer
• [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: 5137).
• [3] Anastrozole FDA Label
• [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: 7731).
• [5] Phase II Study of Saracatinib (AZD0530) in Patients With Previously Treated Metastatic Colorectal Cancer. Invest New Drugs. 2015 Aug;33(4):977-84.
• [6] Saracatinib Inhibits Middle East Respiratory Syndrome-Coronavirus Replication In Vitro. Viruses. 2018 May 24;10(6). pii: E283.
• [7] Effective aromatase inhibition by anastrozole in a patient with gonadotropin-independent precocious puberty in McCune-Albright syndrome. J Pediatr Endocrinol Metab. 2002;15 Suppl 3:945-8.
• [8] Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2. Clin Pharmacol Ther. 2019 Jan 16.
• [9] In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010 Dec;70(6):854-69.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Assessment of Five Pesticides as Endocrine-Disrupting Chemicals: Effects on Estrogen Receptors and Aromatase. Int J Environ Res Public Health. 2022 Feb 10;19(4):1959. doi: 10.3390/ijerph19041959.
• [14] Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol. 2018 Jan 1;338:182-190. doi: 10.1016/j.taap.2017.11.020. Epub 2017 Nov 24.
• [15] Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005 Apr 10;23(11):2477-92. doi: 10.1200/JCO.2005.07.559. Epub 2005 Mar 14.
• [16] Novel dual Src/Abl inhibitors for hematologic and solid malignancies.Expert Opin Investig Drugs.2010 Aug;19(8):931-45.
• [17] A novel bile acid-activated vitamin D receptor signaling in human hepatocytes. Mol Endocrinol. 2010 Jun;24(6):1151-64.
• [18] L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis. FASEB J. 2018 Mar;32(3):1364-1374. doi: 10.1096/fj.201700970. Epub 2018 Jan 3.
• [19] Identification of PKMYT1 inhibitors by screening the GSK published protein kinase inhibitor set I and II. Bioorg Med Chem. 2018 Aug 7;26(14):4014-4024. doi: 10.1016/j.bmc.2018.06.027. Epub 2018 Jun 20.
• [20] Cytochrome P450 Mediated Bioactivation of Saracatinib. Chem Res Toxicol. 2016 Nov 21;29(11):1835-1842. doi: 10.1021/acs.chemrestox.6b00242. Epub 2016 Nov 3.