Details of the Drug Combination

General Information of Drug Combination (ID: DCKCOWC)

Drug Combination Name

GDC-0980/RG7422 Trametinib

Indication

Disease Entry	Status	REF
Embryonal rhabdomyosarcoma	Investigative	[1]

Component Drugs

GDC-0980/RG7422 DMF3MV1

Trametinib DM2JGQ3

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: RD

Zero Interaction Potency (ZIP) Score: 22.472

Bliss Independence Score: 22.075

Loewe Additivity Score: 18.351

LHighest Single Agent (HSA) Score: 20.536

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of GDC-0980/RG7422

Disease Entry	ICD 11	Status	REF
Non-hodgkin lymphoma	2B33.5	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

GDC-0980/RG7422 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Modulator	[8]
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Modulator	[9]
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GDC-0980/RG7422 Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD)	OTOMP6TH	PK3CD_HUMAN	Decreases Activity	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[9]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[9]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[9]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[9]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB)	OTO8JQJA	PK3CB_HUMAN	Decreases Activity	[9]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG)	OT3FAU4Y	PK3CG_HUMAN	Decreases Activity	[9]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[7]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Increases Expression	[7]
Tuberin (TSC2)	OT47LWI9	TSC2_HUMAN	Decreases Phosphorylation	[10]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[7]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[10]
Cyclin-G2 (CCNG2)	OTII38K2	CCNG2_HUMAN	Increases Expression	[7]
Atos homolog protein A (ATOSA)	OTWFM5G0	ATOSA_HUMAN	Increases Expression	[7]
Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1)	OTWE5G4T	P3IP1_HUMAN	Increases Expression	[7]
Serine/threonine-protein kinase STK11 (STK11)	OT1YZSP3	STK11_HUMAN	Increases Response To Substance	[7]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Response To Substance	[7]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Response To Substance	[7]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Increases Response To Substance	[7]
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⏷ Show the Full List of 19 DOT(s)

Indication(s) of Trametinib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[4]
Metastatic melanoma	2E2Z	Approved	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[6]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[6]

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	[11]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[6]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[6]
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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	[12]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[12]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[12]
Tumor necrosis factor receptor superfamily member 16 (NGFR)	OTPKSM49	TNR16_HUMAN	Increases Expression	[13]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[12]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[12]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Phosphorylation	[14]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[13]
Guanine nucleotide-binding protein subunit alpha-11 (GNA11)	OT0K99TO	GNA11_HUMAN	Increases Response To Substance	[12]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Decreases Response To Substance	[15]
Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ)	OTOODWTU	GNAQ_HUMAN	Increases Response To Substance	[12]
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⏷ Show the Full List of 13 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Glioblastoma	DCLB79G	JHH-136	Investigative	[16]
Embryonal rhabdomyosarcoma	DCFTAZX	Rh36	Investigative	[1]
Embryonal rhabdomyosarcoma	DCHE4QO	CTR	Investigative	[1]
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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	Clinical pipeline report, company report or official report of Roche.
3	Clinical pipeline report, company report or official report of Genentech (2011).
4	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).
5	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
6	Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
7	Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res. 2012 Dec 15;18(24):6771-83. doi: 10.1158/1078-0432.CCR-12-2347. Epub 2012 Nov 7.
8	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. (Target id: 2109).
9	GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011 Dec;10(12):2426-36.
10	Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. Mol Cancer Ther. 2012 Jul;11(7):1510-7. doi: 10.1158/1535-7163.MCT-11-0907. Epub 2012 Apr 24.
11	Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
12	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.
13	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.
14	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.
15	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.
16	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.