Details of the Drug Combination

General Information of Drug Combination (ID: DCAF96A)

• Drug Combination Name: LY2835219 + Tamoxifen
• Indication: Male Breast Cancer; Status: Phase 2 [1]
• Component Drugs:
  LY2835219 (DM93VBZ): Small molecular drug
  Tamoxifen (DMLB0EZ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of LY2835219

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[3]

LY2835219 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 4 (CDK4)	TT0PG8F	CDK4_HUMAN	Modulator	[7]
Cyclin-dependent kinase 6 (CDK6)	TTO0FDJ	CDK6_HUMAN	Modulator	[7]

LY2835219 Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[8]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[8]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[8]

LY2835219 Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]

LY2835219 Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tripeptidyl-peptidase 1 (TPP1)	OT2LQ771	TPP1_HUMAN	Increases Expression	[6]
Glutaminase kidney isoform, mitochondrial (GLS)	OTGOZG2M	GLSK_HUMAN	Increases Expression	[6]
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[6]
Securin (PTTG1)	OTIMYS4W	PTTG1_HUMAN	Decreases Expression	[6]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[10]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Increases Expression	[6]
Fibrinogen beta chain (FGB)	OT6RKLI9	FIBB_HUMAN	Decreases Expression	[6]
Fibrinogen gamma chain (FGG)	OT5BJSEX	FIBG_HUMAN	Decreases Expression	[6]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Expression	[6]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[10]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[11]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[6]
SPARC (SPARC)	OTPN90H0	SPRC_HUMAN	Increases Expression	[6]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Affects Expression	[12]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[10]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Affects Expression	[12]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[12]
Ran-specific GTPase-activating protein (RANBP1)	OTQE226K	RANG_HUMAN	Decreases Expression	[6]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[6]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Expression	[12]
Ephrin-B3 (EFNB3)	OT12WTXQ	EFNB3_HUMAN	Decreases Expression	[6]
Insulin growth factor-like family member 2 (IGFL2)	OT64M0K7	IGFL2_HUMAN	Increases Expression	[6]
BRCA1-associated RING domain protein 1 (BARD1)	OTTC0Z9Y	BARD1_HUMAN	Decreases Expression	[6]
Fanconi anemia group E protein (FANCE)	OTKRPBW1	FANCE_HUMAN	Decreases Expression	[6]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[11]
Transforming acidic coiled-coil-containing protein 3 (TACC3)	OTRNEZTA	TACC3_HUMAN	Decreases Expression	[6]

Indication(s) of Tamoxifen

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[4]
Inflammatory breast cancer	2C62	Approved	[5]
Invasive ductal breast carcinoma	N.A.	Approved	[5]

Tamoxifen Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[13]

Tamoxifen Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[15]
Multidrug resistance-associated protein 7 (ABCC10)	DTPS120	MRP7_HUMAN	Substrate	[16]

Tamoxifen Interacts with 16 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[19]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[20]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[21]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[22]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[23]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[24]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[20]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[25]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[26]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[28]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[29]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[30]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[31]

Tamoxifen Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Coagulation factor V (F5)	OTDMZ3LT	FA5_HUMAN	Increases ADR	[32]

References

• [1] ClinicalTrials.gov (NCT05501704) ETHAN - ET for Male BC
• [2] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [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: 7382).
• [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: 1016).
• [5] Tamoxifen FDA Label
• [6] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [7] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [8] Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate. Clin Pharmacol Ther. 2019 May;105(5):1187-1195.
• [9] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]-Abemaciclib.
• [10] CDK4/6 Inhibition Controls Proliferation of Bladder Cancer and Transcription of RB1. J Urol. 2016 Mar;195(3):771-9. doi: 10.1016/j.juro.2015.08.082. Epub 2015 Aug 28.
• [11] Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2017 Jan 15;124:29-42. doi: 10.1016/j.bcp.2016.10.015. Epub 2016 Nov 2.
• [12] In vitro therapeutic effects of abemaciclib on triple-negative breast cancer cells. J Biochem Mol Toxicol. 2021 Sep;35(9):e22858. doi: 10.1002/jbt.22858. Epub 2021 Jul 26.
• [13] Modulators of vascular sex hormone receptors and their effects in estrogen-deficiency states associated with menopause. Recent Pat Cardiovasc Drug Discov. 2008 Nov;3(3):165-86.
• [14] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [15] The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters. Cancer Lett. 2016 Jun 28;376(1):165-72.
• [16] Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7). Cancer Res. 2012 Dec 15;72(24):6457-67.
• [17] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [18] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [19] Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009 Mar 1;69(5):1892-900.
• [20] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [21] Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
• [22] Tamoxifen-induced adduct formation and cell stress in human endometrial glands. Drug Metab Dispos. 2010 Jan;38(1):200-7.
• [23] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [24] Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
• [25] Polymorphism of estrogen metabolism genes and cataract. Med Hypotheses. 2004;63(3):494-7.
• [26] Drug Interactions Flockhart Table
• [27] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [28] Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
• [29] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [30] Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22.
• [31] Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos. 2007 Nov;35(11):2006-14.
• [32] Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst. 2010 Jul 7;102(13):942-9. doi: 10.1093/jnci/djq211. Epub 2010 Jun 16.