Drug Information

Drug (ID: DG01520) and It's Reported Resistant Information

• Name: RAF-265
• Synonyms: RAF265; 927880-90-8; CHIR-265; RAF 265; RAF-265; RAF265(CHIR-265); CHIR 265; RAF265 (CHIR-265); 1-Methyl-5-[[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]-4-pyridinyl]oxy]-n-[4-(trifluoromethyl)phenyl]-1h-benzimidazol-2-amine; 1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine; CHIR265; UNII-8O434L3768; RAF-265 (CHIR-265); 8O434L3768; 1-Methyl-5-({2-[5-(Trifluoromethyl)-1h-Imidazol-2-Yl]pyridin-4-Yl}oxy)-N-[4-(Trifluoromethyl)phenyl]-1h-Benzimidazol-2-Amine; 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine; 1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]-oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine; NVP-RAF265; SCHEMBL686452; CHEMBL558752; GTPL5674; BDBM31088; C24H16F6N6O; CHEBI:91451; EX-A072; cid_11656518; HMS3655B06; HMS3672I21; AMY24172; AOB87162; RAF265 - CHIR-265; MFCD16659061; NSC754357; NSC800861; s2161; ZINC18710085; CHIR 265 (RAF 265); AKOS025117575; CCG-264703; CS-0232; DB05984; EX-8671; NSC-754357; NSC-800861; SB16578; NCGC00250407-01; NCGC00250407-04; 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine; AC-30291; AS-56738; HY-10248; QC-11760; FT-0746327; SW219923-1; X7407; A25488; J-504965; Q27075961; [1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridyl]oxy]benzimidazol-2-yl]-[4-(trifluoromethyl)phenyl]amine; {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzo-imidazol-2-yl}-(4-trifluoromethyl-phenyl)-amine; {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)-amine; 1-methyl-5-({2-[4-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl}oxy)-N-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazol-2-amine; 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine; 1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)pyridin-4-yloxy]-N-(4-trifluoromethylphenyl)-1H-benzo[d]imidazol-2-amine; 1H-Benzimidazol-2-amine, 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)-4-pyridinyl)oxy)-N-(4-(trifluoromethyl)phenyl)-; 1H-Benzimidazol-2-amine, 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]; 55J; CHIR-265;1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine
• Indication:
  In total 1 Indication(s)
  Non-small-cell lung cancer [ICD-11: 2C25]; Phase 2; [1]
• Target: ALK tyrosine kinase receptor (ALK); ALK_HUMAN; [2]
• Target: HGF/Met signaling pathway (HGF/Met pathway); NOUNIPROTAC; [2]
• Target: Proto-oncogene c-Met (MET); MET_HUMAN; [2]
• Target: Proto-oncogene c-Ros (ROS1); ROS1_HUMAN; [2]
• Formula: 5
• IsoSMILES: CN1C2=C(C=C(C=C2)OC3=CC(=NC=C3)C4=NC=C(N4)C(F)(F)F)N=C1NC5=CC=C(C=C5)C(F)(F)F
• InChI: InChI=1S/C24H16F6N6O/c1-36-19-7-6-15(10-17(19)34-22(36)33-14-4-2-13(3-5-14)23(25,26)27)37-16-8-9-31-18(11-16)21-32-12-20(35-21)24(28,29)30/h2-12H,1H3,(H,32,35)(H,33,34)
• InChIKey: YABJJWZLRMPFSI-UHFFFAOYSA-N
• PubChem CID: 11656518
• ChEBI ID: CHEBI:91451
• TTD Drug ID: D03ZBT
• DrugBank ID: DB05984

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: BRAF kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of RAF-265 by aberration of the drug's therapeutic target

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.

References

• Ref 1: A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation statusCancer Med. 2017 Aug;6(8):1904-1914. doi: 10.1002/cam4.1140. Epub 2017 Jul 18.
• Ref 2: Gatekeeper mutations mediate resistance to BRAF-targeted therapiesSci Transl Med. 2010 Jun 9;2(35):35ra41. doi: 10.1126/scitranslmed.3000758.