Details of the Drug Combination

General Information of Drug Combination (ID: DCCGPAR)

Drug Combination Name

Trametinib Abexinostat

Indication

Disease Entry	Status	REF
Diffuse intrinsic pontine glioma	Investigative	[1]

Component Drugs

Trametinib DM2JGQ3

Abexinostat DM91LGU

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: DIPG25

Zero Interaction Potency (ZIP) Score: 20.439

Bliss Independence Score: 20.4

Loewe Additivity Score: 22.74

LHighest Single Agent (HSA) Score: 25.158

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Trametinib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[2]
Metastatic melanoma	2E2Z	Approved	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[4]

Trametinib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[7]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[4]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[4]
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Trametinib Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[8]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[8]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[8]
Tumor necrosis factor receptor superfamily member 16 (NGFR)	OTPKSM49	TNR16_HUMAN	Increases Expression	[9]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[8]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[8]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[8]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Phosphorylation	[10]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[9]
Guanine nucleotide-binding protein subunit alpha-11 (GNA11)	OT0K99TO	GNA11_HUMAN	Increases Response To Substance	[8]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Decreases Response To Substance	[11]
Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ)	OTOODWTU	GNAQ_HUMAN	Increases Response To Substance	[8]
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⏷ Show the Full List of 13 DOT(s)

Indication(s) of Abexinostat

Disease Entry	ICD 11	Status	REF
Follicular lymphoma	2A80	Phase 3	[5]
Renal cell carcinoma	2C90	Phase 3	[6]
Acute myeloid leukaemia	2A60	Phase 2	[5]
Breast cancer	2C60-2C65	Phase 2	[5]
Diffuse large B-cell lymphoma	2A81	Phase 2	[5]
Gynecologic cancer	2F33-2F76	Phase 2	[5]
Peripheral T-cell lymphoma	2A90.C	Phase 2	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]

Abexinostat Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histone deacetylase (HDAC)	TTBH0VX	NOUNIPROTAC	Modulator	[13]
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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	[12]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)	OT8V1J4M	GA45G_HUMAN	Increases Expression	[14]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[12]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[12]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[14]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Decreases Expression	[12]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[12]
Heme oxygenase 2 (HMOX2)	OTG40XBT	HMOX2_HUMAN	Decreases Expression	[12]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[12]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[14]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[12]
C-C motif chemokine 7 (CCL7)	OTDIS99H	CCL7_HUMAN	Decreases Expression	[12]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Decreases Expression	[12]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[14]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[12]
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⏷ Show the Full List of 15 DOT(s)

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	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: 6495).
3	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4	Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
5	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6	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.
7	Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
8	Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25.
9	Harnessing autophagy to overcome mitogen-activated protein kinase kinase inhibitor-induced resistance in metastatic melanoma. Br J Dermatol. 2019 Feb;180(2):346-356. doi: 10.1111/bjd.17333. Epub 2018 Nov 25.
10	Physapubescin B enhances the sensitivity of gastric cancer cells to trametinib by inhibiting the STAT3 signaling pathway. Toxicol Appl Pharmacol. 2020 Dec 1;408:115273. doi: 10.1016/j.taap.2020.115273. Epub 2020 Oct 6.
11	Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2018 Sep;65(9):e27237. doi: 10.1002/pbc.27237. Epub 2018 May 16.
12	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.
13	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.
14	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.