Details of the Drug Combination

General Information of Drug Combination (ID: DCVMQMU)

• Drug Combination Name: Lonafarnib + Anastrozole
• Indication: Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Lonafarnib (DMGM2Z6): Small molecular drug
  Anastrozole (DMNP60F): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lonafarnib

Disease Entry	ICD 11	Status	REF
Hutchinson-Gilford progeria syndrome	LD2B	Approved	[2]
Myelodysplastic syndrome	2A37	Phase 3	[3]
Hepatitis D virus infection	1E51.2	Phase 2	[4]
Non-small-cell lung cancer	2C25.Y	Discontinued in Phase 3	[5]

Lonafarnib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Farnesyl protein transferase (Ftase)	TTXQKM3	FNTA_HUMAN; FNTB_HUMAN	Modulator	[2]

Lonafarnib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[8]

Lonafarnib Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prelamin-A/C (LMNA)	OT3SG7ZR	LMNA_HUMAN	Decreases Farnesylation	[9]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[10]
GTP-binding protein Rheb (RHEB)	OTFLTSEC	RHEB_HUMAN	Decreases Activity	[11]

Indication(s) of Anastrozole

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[6]
Estrogen-receptor positive breast cancer	N.A.	Approved	[7]
Obesity	5B81	Approved	[7]

Anastrozole Interacts with 1 DTT Molecule(s)

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

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	[13]

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	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[14]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[14]

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	[15]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[16]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[17]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Decreases Activity	[18]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Decreases Expression	[19]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[20]

References

• [1] ClinicalTrials.gov (NCT00081510) Anastrozole Plus Lonafarnib (SCH 66336) or Plus Placebo for the Treatment of Advanced Breast Cancer (P03480)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [3] ClinicalTrials.gov (NCT00109538) Study of Lonafarnib Versus Placebo in Subjects With Either Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) (Study P02978AM3)(TERMINATED). U.S. National Institutes of Health.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 8024).
• [6] 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).
• [7] Anastrozole FDA Label
• [8] Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35.
• [9] Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma. Leuk Res. 2007 Mar;31(3):341-52. doi: 10.1016/j.leukres.2006.07.018. Epub 2006 Sep 22.
• [10] The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood. 2005 Dec 15;106(13):4322-9. doi: 10.1182/blood-2005-06-2584. Epub 2005 Aug 23.
• [11] Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 2010 Nov 1;297(1):117-25. doi: 10.1016/j.canlet.2010.05.004.
• [12] 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.
• [13] Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2. Clin Pharmacol Ther. 2019 Jan 16.
• [14] In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010 Dec;70(6):854-69.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.