Details of the Drug Combination

General Information of Drug Combination (ID: DCA8K1H)

• Drug Combination Name: CB-839 + Cabozantinib
• Indication: Advanced Renal Cell Carcinoma; Status: Phase 2 [1]
• Component Drugs:
  CB-839 (DM094UH): N.A.
  Cabozantinib (DMIYDT4): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of CB-839

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 2	[2]
Renal cell carcinoma	2C90	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]
leukaemia	2A60-2B33	Phase 1	[3]

CB-839 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutaminase (GLS)	TTCW0KX	GLSK_HUMAN; GLSL_HUMAN	Modulator	[6]

CB-839 Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutaminase kidney isoform, mitochondrial (GLS)	OTGOZG2M	GLSK_HUMAN	Decreases Activity	[7]

Indication(s) of Cabozantinib

Disease Entry	ICD 11	Status	REF
Medullary thyroid gland carcinoma	N.A.	Approved	[4]
Thyroid cancer	2D10	Approved	[5]
Ovarian cancer	2C73	Phase 2	[5]

Cabozantinib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proto-oncogene c-Met (MET)	TTNDSF4	MET_HUMAN	Inhibitor	[8]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[8]

Cabozantinib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]

Cabozantinib Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Phosphorylation	[11]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[12]

References

• [1] ClinicalTrials.gov (NCT03428217) CANTATA: CB-839 With Cabozantinib vs. Cabozantinib With Placebo in Patients With Metastatic Renal Cell Carcinoma
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] ClinicalTrials.gov (NCT02071862) Study of the Glutaminase Inhibitor CB-839 in Solid Tumors. U.S. National Institutes of Health.
• [4] Cabozantinib FDA Label
• [5] 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: 5887).
• [6] Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014 Apr;13(4):890-901.
• [7] Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. J Biol Chem. 2019 Jun 14;294(24):9342-9357.
• [8] Clinical pipeline report, company report or official report of Exelixis (2011).
• [9] Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. Onco Targets Ther. 2017 Oct 19;10:5053-5064.
• [10] FDA Label of Cabozantinib. The 2020 official website of the U.S. Food and Drug Administration.
• [11] ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway. Toxicol Appl Pharmacol. 2019 Nov 15;383:114768. doi: 10.1016/j.taap.2019.114768. Epub 2019 Oct 19.
• [12] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.