Details of the Drug Combination

General Information of Drug Combination (ID: DCXEWGI)

• Drug Combination Name: ABT-263 + Carfilzomib
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  ABT-263 (DMNE56X): Small molecular drug
  Carfilzomib (DM48K0X): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 4.804
  Bliss Independence Score: 3.381
  Loewe Additivity Score: 2.232
  LHighest Single Agent (HSA) Score: 5.786

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ABT-263

Disease Entry	ICD 11	Status	REF
Myelofibrosis	2A20.2	Phase 3	[2]
Relapsed or refractory chronic lymphocytic leukaemia	2A82.0	Phase 2	[3]
Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[4]

ABT-263 Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-W (BCL-W)	TTQ79W8	B2CL2_HUMAN	Inhibitor	[8]
G1/S-specific cyclin-D1 (CCND1)	TTFCJ7S	CCND1_HUMAN	Inhibitor	[7]
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Inhibitor	[8]
Apoptosis regulator Bcl-xL (BCL-xL)	TTU1E82	B2CL1_HUMAN	Inhibitor	[8]

ABT-263 Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

ABT-263 Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

ABT-263 Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[11]
Gelsolin (GSN)	OT4KS2UU	GELS_HUMAN	Increases Cleavage	[12]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[12]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Affects Response To Substance	[11]

Indication(s) of Carfilzomib

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Approved	[5]
Plasma cell myeloma	2A83.1	Approved	[6]
Small-cell lung cancer	2C25.Y	Phase 1/2	[7]

Carfilzomib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proteasome (PS)	TTU7ZMG	NOUNIPROTAC	Modulator	[14]

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	[15]

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	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[17]
Cytochrome c oxidase subunit 8A, mitochondrial (COX8A)	OTU0NR39	COX8A_HUMAN	Decreases Expression	[17]
Basigin (BSG)	OTD0CVEC	BASI_HUMAN	Decreases Expression	[18]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[18]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Decreases Expression	[18]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Activity	[17]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Response To Substance	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Glioblastoma	DC2UMYK	JHH-136	Investigative	[1]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [2] ClinicalTrials.gov (NCT04472598) Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis (TRANSFORM-1). U.S. National Institutes of Health.
• [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: 8319).
• [4] Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.Nat Rev Drug Discov. 2016 Aug;15(8):533-50.
• [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: 7420).
• [6] Carfilzomib FDA Label
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Clinical pipeline report, company report or official report of Roche (2009).
• [9] The B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoprotein. Biochem Biophys Res Commun. 2011 May 6;408(2):344-9.
• [10] Effect of rifampin on the pharmacokinetics, safety and tolerability of navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-XL , in patients with cancer. J Clin Pharm Ther. 2014 Dec;39(6):680-4.
• [11] Human breast cancer cells display different sensitivities to ABT-263 based on the level of survivin. Toxicol In Vitro. 2018 Feb;46:229-236. doi: 10.1016/j.tiv.2017.09.023. Epub 2017 Sep 23.
• [12] BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood. 2011 Jun 30;117(26):7145-54. doi: 10.1182/blood-2011-03-344812. Epub 2011 May 11.
• [13] 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.
• [14] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration. Oncotarget. 2016 Nov 22;7(47):77543-77557. doi: 10.18632/oncotarget.12721.
• [19] Suppression of BRCA1 sensitizes cells to proteasome inhibitors. Cell Death Dis. 2014 Dec 18;5(12):e1580. doi: 10.1038/cddis.2014.537.