Details of the Drug Combination

General Information of Drug Combination (ID: DCSGUYD)

• Drug Combination Name: ABT-263 + NVP-AUY922
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  ABT-263 (DMNE56X): Small molecular drug
  NVP-AUY922 (DMTYXQF): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 9.97
  Bliss Independence Score: 7.613
  Loewe Additivity Score: 1.257
  LHighest Single Agent (HSA) Score: 4.579

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	[7]
G1/S-specific cyclin-D1 (CCND1)	TTFCJ7S	CCND1_HUMAN	Inhibitor	[8]
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Inhibitor	[7]
Apoptosis regulator Bcl-xL (BCL-xL)	TTU1E82	B2CL1_HUMAN	Inhibitor	[7]

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 NVP-AUY922

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Phase 2	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]

NVP-AUY922 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Heat shock protein 90 alpha (HSP90A)	TT78R5H	HS90A_HUMAN	Inhibitor	[14]

NVP-AUY922 Interacts with 35 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Anterior gradient protein 2 homolog (AGR2)	OTRRZT7W	AGR2_HUMAN	Increases Expression	[13]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[15]
Fibroblast growth factor 1 (FGF1)	OT8I64X8	FGF1_HUMAN	Decreases Expression	[13]
ATP synthase subunit beta, mitochondrial (ATP5F1B)	OTLFZUQK	ATPB_HUMAN	Decreases Expression	[13]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[15]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Expression	[15]
Platelet-derived growth factor receptor beta (PDGFRB)	OTYSNK9Q	PGFRB_HUMAN	Decreases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[13]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[15]
S-formylglutathione hydrolase (ESD)	OTUSIBPS	ESTD_HUMAN	Increases Expression	[13]
Elongation factor 2 (EEF2)	OTZ7SZ39	EF2_HUMAN	Increases Expression	[13]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Decreases Expression	[13]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Decreases Expression	[15]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Decreases Expression	[13]
Intron Large complex component GCFC2 (GCFC2)	OTC7FRXL	GCFC2_HUMAN	Increases Expression	[13]
Proteasome subunit alpha type-1 (PSMA1)	OTNBVM2U	PSA1_HUMAN	Increases Expression	[13]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Affects Phosphorylation	[15]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[15]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[15]
Radixin (RDX)	OTNSYUN6	RADI_HUMAN	Increases Expression	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[15]
Serpin H1 (SERPINH1)	OTKGI7BS	SERPH_HUMAN	Decreases Expression	[13]
Small ubiquitin-related modifier 3 (SUMO3)	OTTUJQJ1	SUMO3_HUMAN	Decreases Expression	[13]
Peptidyl-prolyl cis-trans isomerase A (PPIA)	OTHJMWQQ	PPIA_HUMAN	Increases Expression	[13]
Echinoderm microtubule-associated protein-like 5 (EML5)	OT0EFCPB	EMAL5_HUMAN	Increases Expression	[13]
Interleukin enhancer-binding factor 3 (ILF3)	OTKMZ5K5	ILF3_HUMAN	Decreases Expression	[13]
Eukaryotic translation initiation factor 3 subunit I (EIF3I)	OTE07WND	EIF3I_HUMAN	Decreases Expression	[13]
3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10)	OT7RJON4	HCD2_HUMAN	Decreases Expression	[13]
Phenylalanine--tRNA ligase beta subunit (FARSB)	OT8N9TT5	SYFB_HUMAN	Increases Expression	[13]
Protein PALS2 (PALS2)	OTV12NKE	PALS2_HUMAN	Increases Expression	[13]
Cingulin (CGN)	OTBCQ8AQ	CING_HUMAN	Decreases Expression	[13]
Poly polymerase 2 (PARP2)	OTYL81ZI	PARP2_HUMAN	Increases Expression	[13]
Hypoxia up-regulated protein 1 (HYOU1)	OTBGBSOV	HYOU1_HUMAN	Decreases Expression	[13]
Phosphoserine aminotransferase (PSAT1)	OTVV1YV9	SERC_HUMAN	Increases Expression	[13]

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] ClinicalTrials.gov (NCT01854034) Phase 2 Study of AUY922 in NSCLC Patients With Exon 20 Insertion Mutations in EGFR. U.S. National Institutes of Health.
• [6] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027019)
• [7] Clinical pipeline report, company report or official report of Roche (2009).
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [14] Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem. 2008 Oct;8(7):761-82.
• [15] Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma. Cancer. 2013 Jan 15;119(2):293-303. doi: 10.1002/cncr.27743. Epub 2012 Jul 18.