Details of the Drug Combination

General Information of Drug Combination (ID: DC0G6QD)

• Drug Combination Name: Infigratinib + Trametinib
• Indication: Embryonal rhabdomyosarcoma; Status: Investigative [1]
• Component Drugs:
  Infigratinib (DMNKBEC): Small molecular drug
  Trametinib (DM2JGQ3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: RD
  Zero Interaction Potency (ZIP) Score: 13.996
  Bliss Independence Score: 15.173
  Loewe Additivity Score: 8.469
  LHighest Single Agent (HSA) Score: 9.819

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Infigratinib

Disease Entry	ICD 11	Status	REF
Cholangiocarcinoma	2C12.10	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]

Infigratinib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Fibroblast growth factor receptor (FGFR)	TT0LF7H	NOUNIPROTAC	Inhibitor	[7]
Fibroblast growth factor receptor 1 (FGFR1)	TTRLW2X	FGFR1_HUMAN	Modulator	[8]

Infigratinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Increases Response To Substance	[9]

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	[10]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[6]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[6]

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

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Embryonal rhabdomyosarcoma	DCK2VEK	Rh36	Investigative	[1]
Embryonal rhabdomyosarcoma	DCXWIX9	CTR	Investigative	[1]

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] FDA Approved Drug Products from FDA Official Website. 2021. Application Number: 214622.
• [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: 7877).
• [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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res. 2013 Apr;28(4):899-911.
• [9] Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011 Oct 27;54(20):7066-83. doi: 10.1021/jm2006222. Epub 2011 Sep 21.
• [10] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.