Details of the Drug Combination

General Information of Drug Combination (ID: DC6IN7U)

• Drug Combination Name: Clarithromycin + LY2835219
• Indication: Neoplasm; Status: Phase 1 [1]
• Component Drugs:
  Clarithromycin (DM4M1SG): Small molecular drug: 3D MOL is unavailable
  LY2835219 (DM93VBZ): Small molecular drug: 3D MOL is unavailable

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clarithromycin

Disease Entry	ICD 11	Status	REF
Acute maxillary sinusitis	N.A.	Approved	[2]
Acute otitis media	AB00	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Streptococcal pneumonia	N.A.	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Pneumonia caused by chlamydia	N.A.	Investigative	[2]

Clarithromycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 50S ribosomal RNA (Bact 50S rRNA)	TTUWYEA	NOUNIPROTAC	Binder	[7]

Clarithromycin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Clarithromycin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Clarithromycin Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[12]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[13]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Decreases Expression	[14]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Decreases Expression	[14]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[14]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[16]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[17]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[18]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Integrin beta-4 (ITGB4)	OT28UK84	ITB4_HUMAN	Decreases Expression	[20]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[21]
Translation initiation factor IF-2, mitochondrial (MTIF2)	OTAIOZ0J	IF2M_HUMAN	Decreases Response To Substance	[16]
Misshapen-like kinase 1 (MINK1)	OTKB0RA8	MINK1_HUMAN	Increases ADR	[21]

Indication(s) of LY2835219

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[6]

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	[23]
Cyclin-dependent kinase 6 (CDK6)	TTO0FDJ	CDK6_HUMAN	Modulator	[23]

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	[24]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[24]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[24]

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	[25]

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	[22]
Glutaminase kidney isoform, mitochondrial (GLS)	OTGOZG2M	GLSK_HUMAN	Increases Expression	[22]
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[22]
Securin (PTTG1)	OTIMYS4W	PTTG1_HUMAN	Decreases Expression	[22]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[26]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Increases Expression	[22]
Fibrinogen beta chain (FGB)	OT6RKLI9	FIBB_HUMAN	Decreases Expression	[22]
Fibrinogen gamma chain (FGG)	OT5BJSEX	FIBG_HUMAN	Decreases Expression	[22]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Expression	[22]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[26]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[27]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[22]
SPARC (SPARC)	OTPN90H0	SPRC_HUMAN	Increases Expression	[22]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Affects Expression	[28]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[26]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Affects Expression	[28]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[22]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[28]
Ran-specific GTPase-activating protein (RANBP1)	OTQE226K	RANG_HUMAN	Decreases Expression	[22]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[22]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Expression	[28]
Ephrin-B3 (EFNB3)	OT12WTXQ	EFNB3_HUMAN	Decreases Expression	[22]
Insulin growth factor-like family member 2 (IGFL2)	OT64M0K7	IGFL2_HUMAN	Increases Expression	[22]
BRCA1-associated RING domain protein 1 (BARD1)	OTTC0Z9Y	BARD1_HUMAN	Decreases Expression	[22]
Fanconi anemia group E protein (FANCE)	OTKRPBW1	FANCE_HUMAN	Decreases Expression	[22]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[27]
Transforming acidic coiled-coil-containing protein 3 (TACC3)	OTRNEZTA	TACC3_HUMAN	Decreases Expression	[22]

References

• [1] ClinicalTrials.gov (NCT02117648) A Study of LY2835219 in Participants With Cancer
• [2] Clarithromycin FDA Label
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• [4] Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early (ACHIEVE)
• [5] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [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: 7382).
• [7] Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001 Oct 25;413(6858):814-21.
• [8] 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.
• [9] Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis. J Cyst Fibros. 2014 Mar;13(2):179-85.
• [10] Drug Interactions Flockhart Table
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• [15] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [16] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.
• [17] Liver toxicity of macrolide antibiotics in zebrafish. Toxicology. 2020 Aug;441:152501. doi: 10.1016/j.tox.2020.152501. Epub 2020 May 23.
• [18] Differential effects of three antibiotics on T helper cell cytokine expression. J Antimicrob Chemother. 2005 Sep;56(3):502-6. doi: 10.1093/jac/dki251. Epub 2005 Jul 8.
• [19] T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest. 2001 Jun;107(11):1433-41. doi: 10.1172/JCI12118.
• [20] Effects of eight antibacterial agents on cell survival and expression of epithelial-cell- or cell-adhesion-related genes in human gingival epithelial cells. J Periodontal Res. 2004 Feb;39(1):50-8. doi: 10.1111/j.1600-0765.2004.00704.x.
• [21] 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.
• [22] 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.
• [23] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [24] Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate. Clin Pharmacol Ther. 2019 May;105(5):1187-1195.
• [25] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]-Abemaciclib.
• [26] 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.
• [27] 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.
• [28] 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.