Details of the Drug Combination

General Information of Drug Combination (ID: DC4FLDV)

• Drug Combination Name: ABT-263 + GSK461364
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  ABT-263 (DMNE56X): Small molecular drug
  GSK461364 (DM0P729): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 30.612
  Bliss Independence Score: 35.362
  Loewe Additivity Score: 2.562
  LHighest Single Agent (HSA) Score: 4.338

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	[6]
G1/S-specific cyclin-D1 (CCND1)	TTFCJ7S	CCND1_HUMAN	Inhibitor	[7]
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Inhibitor	[6]
Apoptosis regulator Bcl-xL (BCL-xL)	TTU1E82	B2CL1_HUMAN	Inhibitor	[6]

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	[8]

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	[9]

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	[10]
Gelsolin (GSN)	OT4KS2UU	GELS_HUMAN	Increases Cleavage	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[10]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[11]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[11]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Affects Response To Substance	[10]

Indication(s) of GSK461364

Disease Entry	ICD 11	Status	REF
Non-hodgkin lymphoma	2B33.5	Phase 1	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]

GSK461364 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Polo-like kinase 1 (PLK1)	TTIYVQP	PLK1_HUMAN	Inhibitor	[12]

GSK461364 Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[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] 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: 5684).
• [6] Clinical pipeline report, company report or official report of Roche (2009).
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70.
• [13] A specific inhibitor of polo-like kinase 1, GSK461364A, suppresses proliferation of Raji Burkitt's lymphoma cells through mediating cell cycle arrest, DNA damage, and apoptosis. Chem Biol Interact. 2020 Dec 1;332:109288. doi: 10.1016/j.cbi.2020.109288. Epub 2020 Oct 17.