Details of the Drug Combination

General Information of Drug Combination (ID: DCPOZQT)

• Drug Combination Name: Alpelisib + Zarnestra
• Indication: HNSCC; Status: Phase 1 [1]
• Component Drugs:
  Alpelisib (DMEXMYK): Small molecular drug
  Zarnestra (DMF30HL): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Alpelisib

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

Alpelisib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase alpha (PIK3CA)	TTEUNMR	PK3CA_HUMAN	Inhibitor	[2]

Alpelisib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Indication(s) of Zarnestra

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Phase 3	[4]
Chronic myelogenous leukaemia	2A20.0	Phase 2	[5]
Human papillomavirus infection	1A9Y	Phase 2	[5]
Myelodysplastic syndrome	2A37	Phase 2	[5]
Peripheral T-cell lymphoma	2A90.C	Phase 2	[5]
Colorectal cancer	2B91.Z	Phase 1/2	[6]
Pancreatic cancer	2C10	Phase 1/2	[6]

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	[8]
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[5]

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	[9]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Activity	[10]
GTP-binding protein Rheb (RHEB)	OTFLTSEC	RHEB_HUMAN	Decreases Activity	[11]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Response To Substance	[12]

References

• [1] ClinicalTrials.gov (NCT04997902) Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [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: 7955).
• [4] ClinicalTrials.gov (NCT00093990) Tipifarnib Versus Best Supportive Care in the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML). U.S. National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [7] Comparison of 19F NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans. Drug Metab Dispos. 2017 Aug;45(8):900-907.
• [8] Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008 Sep;2(3):491-500.
• [9] 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.
• [10] 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.
• [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] Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients. Invest New Drugs. 2004 Aug;22(3):285-9.