General Information of Drug Combination (ID: DC4JR8F)

Drug Combination Name
Trametinib GDC-0980/RG7422
Indication
Disease Entry Status REF
Diffuse intrinsic pontine glioma Investigative [1]
Component Drugs Trametinib   DM2JGQ3 GDC-0980/RG7422   DMF3MV1
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: SU-DIPG-XIII
Zero Interaction Potency (ZIP) Score: 11.343
Bliss Independence Score: 10.915
Loewe Additivity Score: 13.487
LHighest Single Agent (HSA) Score: 15.244

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 GDC-0980/RG7422
Disease Entry ICD 11 Status REF
Non-hodgkin lymphoma 2B33.5 Phase 2 [5]
Solid tumour/cancer 2A00-2F9Z Phase 1 [6]
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 [13]
PI3-kinase gamma (PIK3CG) TTHBTOP PK3CG_HUMAN Modulator [14]
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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 [14]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [14]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [14]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [14]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [14]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB) OTO8JQJA PK3CB_HUMAN Decreases Activity [14]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG) OT3FAU4Y PK3CG_HUMAN Decreases Activity [14]
Hepatocyte growth factor receptor (MET) OT7K55MU MET_HUMAN Increases Expression [12]
Receptor tyrosine-protein kinase erbB-3 (ERBB3) OTRSST0A ERBB3_HUMAN Increases Expression [12]
Tuberin (TSC2) OT47LWI9 TSC2_HUMAN Decreases Phosphorylation [15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Decreases Expression [12]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) OTHBQVD5 4EBP1_HUMAN Decreases Phosphorylation [15]
Cyclin-G2 (CCNG2) OTII38K2 CCNG2_HUMAN Increases Expression [12]
Atos homolog protein A (ATOSA) OTWFM5G0 ATOSA_HUMAN Increases Expression [12]
Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1) OTWE5G4T P3IP1_HUMAN Increases Expression [12]
Serine/threonine-protein kinase STK11 (STK11) OT1YZSP3 STK11_HUMAN Increases Response To Substance [12]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Increases Response To Substance [12]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Response To Substance [12]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) OTTOMI8J PK3CA_HUMAN Increases Response To Substance [12]
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⏷ Show the Full List of 19 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 Roche.
6 Clinical pipeline report, company report or official report of Genentech (2011).
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 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.
13 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).
14 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.
15 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.