Details of the Drug Combination

General Information of Drug Combination (ID: DC8FXHY)

• Drug Combination Name: Cantharidin + Cabozantinib
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  Cantharidin (DMBP5N3): Small molecular drug
  Cabozantinib (DMIYDT4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 20.218
  Bliss Independence Score: 25.049
  Loewe Additivity Score: 0.291
  LHighest Single Agent (HSA) Score: 0.012

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cantharidin

Disease Entry	ICD 11	Status	REF
Molluscum contagiosum infection	1E76	Approved	[2]

Cantharidin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine PP1-alpha (PPP1CA)	TTFLH0E	PP1A_HUMAN	Inhibitor	[6]

Cantharidin Interacts with 25 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[5]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Decreases Expression	[7]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[5]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[8]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[5]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Increases Expression	[9]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Expression	[9]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[5]
Calpain-1 catalytic subunit (CAPN1)	OTK6OQZR	CAN1_HUMAN	Increases Expression	[5]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[5]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[10]
Calpain-2 catalytic subunit (CAPN2)	OTIAPE5J	CAN2_HUMAN	Increases Expression	[5]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[9]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Cleavage	[5]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[5]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Decreases Expression	[10]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[5]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[5]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Expression	[10]
Cyclin-dependent kinase 4 inhibitor B (CDKN2B)	OTAG24N1	CDN2B_HUMAN	Affects Expression	[10]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Expression	[5]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[10]
Endonuclease G, mitochondrial (ENDOG)	OT5IM7B3	NUCG_HUMAN	Increases Expression	[5]
Ubiquitin-like-conjugating enzyme ATG3 (ATG3)	OT28VBVK	ATG3_HUMAN	Increases Expression	[9]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[9]

Indication(s) of Cabozantinib

Disease Entry	ICD 11	Status	REF
Medullary thyroid gland carcinoma	N.A.	Approved	[3]
Thyroid cancer	2D10	Approved	[4]
Ovarian cancer	2C73	Phase 2	[4]

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	[11]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[11]

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	[12]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[13]

Cabozantinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Phosphorylation	[14]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Cabozantinib FDA Label
• [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: 5887).
• [5] Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo. Environ Toxicol. 2017 Mar;32(3):723-738. doi: 10.1002/tox.22273. Epub 2016 Apr 25.
• [6] Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies. J Med Chem. 2002 Mar 14;45(6):1151-75.
• [7] Hepatoxicity mechanism of cantharidin-induced liver LO2 cells by LC-MS metabolomics combined traditional approaches. Toxicol Lett. 2020 Oct 15;333:49-61. doi: 10.1016/j.toxlet.2020.07.024. Epub 2020 Jul 26.
• [8] [Apoptosis induced by cantharidin in human pulmonary carcinoma cells A549 and its molecular mechanisms]. Zhonghua Zhong Liu Za Zhi. 2005 Jun;27(6):330-4.
• [9] Endoplasmic reticulum stress contributes to autophagy and apoptosis in cantharidin-induced nephrotoxicity. Food Chem Toxicol. 2022 May;163:112986. doi: 10.1016/j.fct.2022.112986. Epub 2022 Apr 6.
• [10] Cantharidin suppresses gastric cancer cell migration/invasion by inhibiting the PI3K/Akt signaling pathway via CCAT1. Chem Biol Interact. 2020 Feb 1;317:108939. doi: 10.1016/j.cbi.2020.108939. Epub 2020 Jan 13.
• [11] Clinical pipeline report, company report or official report of Exelixis (2011).
• [12] Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. Onco Targets Ther. 2017 Oct 19;10:5053-5064.
• [13] FDA Label of Cabozantinib. The 2020 official website of the U.S. Food and Drug Administration.
• [14] 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.