Details of the Drug Combination

General Information of Drug Combination (ID: DCKX137)

• Drug Combination Name: Carfilzomib + FORMONONETIN
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  Carfilzomib (DM48K0X): Small molecular drug
  FORMONONETIN (DM7WFZ8): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 20.504
  Bliss Independence Score: 20.732
  Loewe Additivity Score: 3.688
  LHighest Single Agent (HSA) Score: 6.336

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Carfilzomib

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[3]
Small-cell lung cancer	2C25.Y	Phase 1/2	[4]

Carfilzomib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proteasome (PS)	TTU7ZMG	NOUNIPROTAC	Modulator	[7]

Carfilzomib 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]

Carfilzomib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[9]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[10]
Cytochrome c oxidase subunit 8A, mitochondrial (COX8A)	OTU0NR39	COX8A_HUMAN	Decreases Expression	[10]
Basigin (BSG)	OTD0CVEC	BASI_HUMAN	Decreases Expression	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[11]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Decreases Expression	[11]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Activity	[10]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Response To Substance	[12]

Indication(s) of FORMONONETIN

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[5]

FORMONONETIN Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
SLC5A2 messenger RNA (SLC5A2 mRNA)	TTF8JAT	SC5A2_HUMAN	Inhibitor	[5]

FORMONONETIN Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[14]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[14]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[15]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Activity	[15]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[15]
Erythropoietin (EPO)	OTZ90CN4	EPO_HUMAN	Increases Expression	[16]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Affects Binding	[17]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[18]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[19]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[19]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Increases Expression	[18]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[18]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[19]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[19]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Expression	[19]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[16]
Estrogen receptor beta (ESR2)	OTXNR2WQ	ESR2_HUMAN	Affects Binding	[20]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[19]

References

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• [2] 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: 7420).
• [3] Carfilzomib FDA Label
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Na+-glucose cotransporter (SGLT) inhibitory flavonoids from the roots of Sophora flavescens. Bioorg Med Chem. 2007 May 15;15(10):3445-9.
• [6] The Zinc-Finger AN1-Type Domain 2a Gene Acts as a Regulator of Cell Survival in Human Melanoma: Role of E3-Ligase cIAP2. Mol Cancer Res. 2019 Dec;17(12):2444-2456. doi: 10.1158/1541-7786.MCR-19-0243. Epub 2019 Sep 20.
• [7] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [8] Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1. Am J Hematol. 2013 Apr;88(4):265-72.
• [9] Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
• [10] Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
• [11] Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration. Oncotarget. 2016 Nov 22;7(47):77543-77557. doi: 10.18632/oncotarget.12721.
• [12] Suppression of BRCA1 sensitizes cells to proteasome inhibitors. Cell Death Dis. 2014 Dec 18;5(12):e1580. doi: 10.1038/cddis.2014.537.
• [13] Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J Biol Chem. 2004 Jan 9;279(2):1429-41.
• [14] In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. Toxicol Lett. 2015 Nov 19;239(1):1-8.
• [15] Red clover aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) agonists enhance genotoxic estrogen metabolism. Chem Res Toxicol. 2017 Nov 20;30(11):2084-2092.
• [16] Flavonoids from Radix Astragali induce the expression of erythropoietin in cultured cells: a signaling mediated via the accumulation of hypoxia-inducible factor-1. J Agric Food Chem. 2011 Mar 9;59(5):1697-704. doi: 10.1021/jf104018u. Epub 2011 Feb 10.
• [17] Estrogenic activity of isoflavonoids from Onobrychis ebenoides. Planta Med. 2006 May;72(6):488-93. doi: 10.1055/s-2005-916261.
• [18] Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury. Toxicol Appl Pharmacol. 2017 Jul 1;326:15-24. doi: 10.1016/j.taap.2017.04.013. Epub 2017 Apr 13.
• [19] Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact. 2013 Oct 5;205(3):188-97. doi: 10.1016/j.cbi.2013.07.003. Epub 2013 Jul 16.
• [20] Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci Biotechnol Biochem. 2002 Jul;66(7):1479-87. doi: 10.1271/bbb.66.1479.