Details of the Drug Combination

General Information of Drug Combination (ID: DC40N2I)

• Drug Combination Name: Zarnestra + Capecitabine
• Indication: Recurrent Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Zarnestra (DMF30HL): Small molecular drug
  Capecitabine (DMTS85L): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Zarnestra

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Phase 3	[2]
Chronic myelogenous leukaemia	2A20.0	Phase 2	[3]
Human papillomavirus infection	1A9Y	Phase 2	[3]
Myelodysplastic syndrome	2A37	Phase 2	[3]
Peripheral T-cell lymphoma	2A90.C	Phase 2	[3]
Colorectal cancer	2B91.Z	Phase 1/2	[4]
Pancreatic cancer	2C10	Phase 1/2	[4]

Zarnestra Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Farnesyl protein transferase (Ftase)	TTXQKM3	FNTA_HUMAN; FNTB_HUMAN	Modulator	[7]
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[3]

Zarnestra Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
GTPase HRas (HRAS)	OTWQN0DP	RASH_HUMAN	Decreases Metabolism	[8]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Activity	[9]
GTP-binding protein Rheb (RHEB)	OTFLTSEC	RHEB_HUMAN	Decreases Activity	[10]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Response To Substance	[11]

Indication(s) of Capecitabine

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[5]
Colon adenocarcinoma	N.A.	Approved	[5]
Colorectal cancer	2B91.Z	Approved	[6]
Metastasis from malignant tumor of colon	N.A.	Approved	[5]
Rectal adenocarcinoma	2B92	Approved	[5]
Breast cancer	2C60-2C65	Phase 3	[6]
Colon cancer	2B90.Z	Investigative	[5]
Gastric cancer	2B72	Investigative	[5]

Capecitabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[14]

Capecitabine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytidine aminohydrolase (CDA)	DEKEDRC	CDD_HUMAN	Metabolism	[15]
Thymidine phosphorylase (TYMP)	DE4HCYL	TYPH_HUMAN	Metabolism	[16]

Capecitabine Interacts with 65 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Dihydropyrimidine dehydrogenase (DPYD)	OTWRF2NR	DPYD_HUMAN	Increases Expression	[17]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[18]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Expression	[18]
C-C motif chemokine 21 (CCL21)	OT7DOXEM	CCL21_HUMAN	Decreases Expression	[12]
CCN family member 1 (CCN1)	OTKJBEMD	CCN1_HUMAN	Decreases Expression	[12]
Aquaporin-8 (AQP8)	OT99JKME	AQP8_HUMAN	Increases Expression	[12]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Decreases Expression	[12]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1)	OTC6GISG	DQA1_HUMAN	Decreases Expression	[12]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[19]
B-lymphocyte antigen CD20 (MS4A1)	OTZTVUBX	CD20_HUMAN	Decreases Expression	[12]
Nuclear receptor subfamily 4immunitygroup A member 1 (NR4A1)	OTGP6GA4	NR4A1_HUMAN	Decreases Expression	[12]
40-kDa huntingtin-associated protein (F8A1)	OTXTQ59R	HAP40_HUMAN	Decreases Expression	[12]
Chloride anion exchanger (SLC26A3)	OTBNK2U2	S26A3_HUMAN	Increases Expression	[12]
Nuclear receptor subfamily 4 group A member 2 (NR4A2)	OT3F9IR2	NR4A2_HUMAN	Decreases Expression	[12]
Potassium-transporting ATPase alpha chain 2 (ATP12A)	OTSQSKEK	AT12A_HUMAN	Increases Expression	[12]
Serine/threonine-protein kinase SIK1 (SIK1)	OT6FCHME	SIK1_HUMAN	Decreases Expression	[12]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Decreases Expression	[12]
Hemoglobin subunit alpha (HBA1)	OTW2BQF4	HBA_HUMAN	Decreases Expression	[12]
Paired box protein Pax-5 (PAX5)	OTYBJJWX	PAX5_HUMAN	Decreases Expression	[12]
Endoplasmic reticulum aminopeptidase 2 (ERAP2)	OTEMENYF	ERAP2_HUMAN	Decreases Expression	[12]
Fc receptor-like A (FCRLA)	OT6MK4M1	FCRLA_HUMAN	Decreases Expression	[12]
Leucine-rich repeat-containing protein 15 (LRRC15)	OTX7JL8H	LRC15_HUMAN	Decreases Expression	[12]
C-C motif chemokine 19 (CCL19)	OTQ2UJMH	CCL19_HUMAN	Decreases Expression	[12]
E3 ubiquitin-protein ligase TRIM31 (TRIM31)	OT7VW6RP	TRI31_HUMAN	Increases Expression	[12]
Interleukin-1 receptor type 2 (IL1R2)	OT0G7E35	IL1R2_HUMAN	Increases Response To Substance	[13]
Interleukin-17 receptor B (IL17RB)	OT0KDNSF	I17RB_HUMAN	Increases Response To Substance	[13]
Glycogen phosphorylase, brain form (PYGB)	OT2ZTJT0	PYGB_HUMAN	Increases Response To Substance	[13]
Calcium and integrin-binding protein 1 (CIB1)	OT4BVCRU	CIB1_HUMAN	Increases Response To Substance	[13]
1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)	OT5I4Y9K	PLCB_HUMAN	Increases Response To Substance	[13]
cAMP-dependent protein kinase catalytic subunit beta (PRKACB)	OT6RMDCE	KAPCB_HUMAN	Decreases Response To Substance	[13]
Claudin-3 (CLDN3)	OT71MN9S	CLD3_HUMAN	Increases Response To Substance	[13]
Replication protein A 70 kDa DNA-binding subunit (RPA1)	OT76POLP	RFA1_HUMAN	Decreases Response To Substance	[13]
Protein flightless-1 homolog (FLII)	OT7G9JG6	FLII_HUMAN	Decreases Response To Substance	[13]
Stress-induced-phosphoprotein 1 (STIP1)	OT7TXLOX	STIP1_HUMAN	Decreases Response To Substance	[13]
Ras-related protein R-Ras2 (RRAS2)	OT83NCEB	RRAS2_HUMAN	Decreases Response To Substance	[13]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Response To Substance	[13]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Response To Substance	[20]
Ras-related protein Rab-40B (RAB40B)	OTCA9ZF5	RB40B_HUMAN	Increases Response To Substance	[13]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Response To Substance	[13]
Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7)	OTDNTHNR	ABCB7_HUMAN	Decreases Response To Substance	[13]
Tyrosine-protein phosphatase non-receptor type 13 (PTPN13)	OTESFZSO	PTN13_HUMAN	Decreases Response To Substance	[13]
ADP-ribosylation factor-like protein 4D (ARL4D)	OTG5I3KU	ARL4D_HUMAN	Decreases Response To Substance	[13]
Double-strand break repair protein MRE11 (MRE11)	OTGU8TZM	MRE11_HUMAN	Decreases Response To Substance	[13]
Inorganic pyrophosphatase (PPA1)	OTHZK1QB	IPYR_HUMAN	Increases Response To Substance	[13]
Polycystin-2 (PKD2)	OTIXBU8H	PKD2_HUMAN	Decreases Response To Substance	[13]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Response To Substance	[13]
Transcriptional activator Myb (MYB)	OTJH64IV	MYB_HUMAN	Increases Response To Substance	[13]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1)	OTJISZOX	PLCE1_HUMAN	Increases Response To Substance	[13]
Plakophilin-2 (PKP2)	OTJOVF68	PKP2_HUMAN	Increases Response To Substance	[13]
Transcriptional enhancer factor TEF-1 (TEAD1)	OTK6971C	TEAD1_HUMAN	Decreases Response To Substance	[13]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Response To Substance	[13]
Myelin regulatory factor (MYRF)	OTKF6AEB	MYRF_HUMAN	Increases Response To Substance	[13]
Galectin-4 (LGALS4)	OTKQCG0H	LEG4_HUMAN	Increases Response To Substance	[13]
Four and a half LIM domains protein 1 (FHL1)	OTN535SU	FHL1_HUMAN	Decreases Response To Substance	[13]
Hepatoma-derived growth factor-related protein 3 (HDGFL3)	OTNN7WYH	HDGR3_HUMAN	Decreases Response To Substance	[13]
E3 ubiquitin-protein ligase TRIM15 (TRIM15)	OTNYAKP6	TRI15_HUMAN	Increases Response To Substance	[13]
Dermatan-sulfate epimerase (DSE)	OTQ108VJ	DSE_HUMAN	Decreases Response To Substance	[13]
Anterior gradient protein 2 homolog (AGR2)	OTRRZT7W	AGR2_HUMAN	Increases Response To Substance	[13]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Increases Response To Substance	[13]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Decreases Response To Substance	[13]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Response To Substance	[13]
3-ketoacyl-CoA thiolase, peroxisomal (ACAA1)	OTVKRET0	THIK_HUMAN	Increases Response To Substance	[13]
Tissue alpha-L-fucosidase (FUCA1)	OTW71IK4	FUCO_HUMAN	Increases Response To Substance	[13]
GTPase HRas (HRAS)	OTWQN0DP	RASH_HUMAN	Decreases Response To Substance	[13]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Increases Response To Substance	[13]

References

• [1] ClinicalTrials.gov (NCT00077363) Capecitabine and Tipifarnib in Treating Women With Taxane-Resistant Metastatic Breast Cancer
• [2] ClinicalTrials.gov (NCT00093990) Tipifarnib Versus Best Supportive Care in the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML). U.S. National Institutes of Health.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [5] Capecitabine FDA Label
• [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: 6799).
• [7] Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008 Sep;2(3):491-500.
• [8] Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells. Blood. 2005 Jun 15;105(12):4759-66. doi: 10.1182/blood-2004-11-4307. Epub 2005 Feb 22.
• [9] Genetic disruption of the PI3K regulatory subunits, p85, p55, and p50, normalizes mutant PTPN11-induced hypersensitivity to GM-CSF. Haematologica. 2012 Jul;97(7):1042-7. doi: 10.3324/haematol.2011.046896. Epub 2012 Feb 7.
• [10] 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.
• [11] Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients. Invest New Drugs. 2004 Aug;22(3):285-9.
• [12] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [13] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [14] UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005 Feb 1;11(3):1226-36.
• [15] Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889. Int J Cancer. 2003 Sep 20;106(5):799-805.
• [16] Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. Mol Cancer Ther. 2002 Oct;1(12):1139-45.
• [17] DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol. 2007 Aug;31(2):413-8.
• [18] Effects of capecitabine and vinorelbine on cell proliferation, metabolism and COX2 and p16 expression in breast cancer cell lines and solid tumour tissues. Biomed Pharmacother. 2007 Oct;61(9):596-600.
• [19] P38 MAPK, NF-B, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression. Chem Res Toxicol. 2022 Mar 21;35(3):422-430. doi: 10.1021/acs.chemrestox.1c00317. Epub 2022 Feb 11.
• [20] A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression. Curr Drug Metab. 2008 May;9(4):336-43. doi: 10.2174/138920008784220646.