Details of the Drug Combination

General Information of Drug Combination (ID: DC4BEMG)

• Drug Combination Name: Carfilzomib + Abexinostat
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Carfilzomib (DM48K0X): Small molecular drug
  Abexinostat (DM91LGU): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 14.388
  Bliss Independence Score: 13.455
  Loewe Additivity Score: 13.754
  LHighest Single Agent (HSA) Score: 21.254

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 Abexinostat

Disease Entry	ICD 11	Status	REF
Follicular lymphoma	2A80	Phase 3	[4]
Renal cell carcinoma	2C90	Phase 3	[5]
Acute myeloid leukaemia	2A60	Phase 2	[4]
Breast cancer	2C60-2C65	Phase 2	[4]
Diffuse large B-cell lymphoma	2A81	Phase 2	[4]
Gynecologic cancer	2F33-2F76	Phase 2	[4]
Peripheral T-cell lymphoma	2A90.C	Phase 2	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]

Abexinostat Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histone deacetylase (HDAC)	TTBH0VX	NOUNIPROTAC	Modulator	[14]

Abexinostat Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[13]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)	OT8V1J4M	GA45G_HUMAN	Increases Expression	[15]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[13]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[13]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Decreases Expression	[13]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[13]
Heme oxygenase 2 (HMOX2)	OTG40XBT	HMOX2_HUMAN	Decreases Expression	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[13]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[15]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[13]
C-C motif chemokine 7 (CCL7)	OTDIS99H	CCL7_HUMAN	Decreases Expression	[13]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Decreases Expression	[13]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[15]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[13]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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] ClinicalTrials.gov (NCT03592472) A Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma (RENAVIV). U.S. National Institutes of Health.
• [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] PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells. Clin Cancer Res. 2009 May 15;15(10):3354-65. doi: 10.1158/1078-0432.CCR-08-2365. Epub 2009 May 5.
• [14] Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia. Invest New Drugs. 2015 Apr;33(2):423-31.
• [15] HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19482-7. doi: 10.1073/pnas.0707828104. Epub 2007 Nov 27.