Details of the Drug Combination

General Information of Drug Combination (ID: DCUZLDF)

• Drug Combination Name: LY2835219 + Exemestane
• Indication: Breast Neoplasms; Status: Phase 1 [1]
• Component Drugs:
  LY2835219 (DM93VBZ): Small molecular drug
  Exemestane (DM9HPW3): 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 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	[13]

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	[14]

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	[15]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[16]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Increases Expression	[16]
Myb-related protein B (MYBL2)	OTZ3JX8Q	MYBB_HUMAN	Increases Expression	[17]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Localization	[18]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[19]
Amphiregulin (AREG)	OTJFOR67	AREG_HUMAN	Increases Expression	[16]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Increases Expression	[17]
Homeobox protein Hox-D11 (HOXD11)	OT9XGA4G	HXD11_HUMAN	Increases Expression	[17]
Pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1)	OTNBHULA	PACR_HUMAN	Increases Expression	[17]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[20]
Kallikrein-7 (KLK7)	OTIWGMO2	KLK7_HUMAN	Increases Expression	[17]
Disabled homolog 2 (DAB2)	OTRMQTMZ	DAB2_HUMAN	Increases Expression	[17]
CD83 antigen (CD83)	OT1V4WQF	CD83_HUMAN	Increases Expression	[17]
Unconventional myosin-IXb (MYO9B)	OTQ94R5K	MYO9B_HUMAN	Increases Expression	[17]
RRP12-like protein (RRP12)	OTQQAEH4	RRP12_HUMAN	Increases Expression	[17]
Dynein axonemal assembly factor 9 (DNAAF9)	OTTKWWQU	DAAF9_HUMAN	Increases Expression	[17]
E3 ubiquitin-protein ligase RNF123 (RNF123)	OTL59S8J	RN123_HUMAN	Increases Expression	[17]
Osteopetrosis-associated transmembrane protein 1 (OSTM1)	OTKNJDH7	OSTM1_HUMAN	Increases Expression	[17]
Glypican-2 (GPC2)	OT3WSQE1	GPC2_HUMAN	Increases Expression	[17]
Tumor necrosis factor receptor superfamily member 14 (TNFRSF14)	OTB82PFO	TNR14_HUMAN	Increases Expression	[17]
Integrator complex subunit 4 (INTS4)	OT5JQ913	INT4_HUMAN	Increases Expression	[17]
Inositol polyphosphate 5-phosphatase K (INPP5K)	OTQFLQKA	INP5K_HUMAN	Increases Expression	[17]
ATP-binding cassette sub-family G member 4 (ABCG4)	OT2XJIOG	ABCG4_HUMAN	Increases Expression	[17]
TRIO and F-actin-binding protein (TRIOBP)	OTGB5WHC	TARA_HUMAN	Increases Expression	[17]
TBC1 domain family member 17 (TBC1D17)	OT75ZWLB	TBC17_HUMAN	Increases Expression	[17]
Kinesin-like protein KIF13B (KIF13B)	OTAFS1YV	KI13B_HUMAN	Increases Expression	[17]
Transcription factor COE1 (EBF1)	OTZ61YYH	COE1_HUMAN	Increases Expression	[17]
Meteorin (METRN)	OTI2645G	METRN_HUMAN	Increases Expression	[17]
Solute carrier family 13 member 4 (SLC13A4)	OTP3N8N3	S13A4_HUMAN	Increases Expression	[17]

References

• [1] ClinicalTrials.gov (NCT02057133) A Study of LY2835219 (Abemaciclib) in Combination With Therapies for Breast Cancer That Has Spread
• [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: 7073).
• [5] Exemestane 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] Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
• [14] 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.
• [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] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.