Drug Information

Drug (ID: DG01603) and It's Reported Resistant Information
Name
Agerafenib
Synonyms
CEP-32496; 1188910-76-0; Agerafenib; CEP 32496; RXDX-105; UNII-78I4VEX88N; 1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea; CEP32496; 78I4VEX88N; CHEMBL2029988; 1-[3-[(6,7-Dimethoxyquinazolin-4-yl)oxy]phenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl]urea; 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea; Rxdx 105; CEP-32496 free base; CEP-32496 (free base); GTPL7880; SCHEMBL1015932; HMS3653J19; BCP16304; EX-A1481; 2310AH; AB-024; BDBM50382959; MFCD22124524; NSC776043; NSC800070; s8015; ZINC43207440; AKOS023600525; AKOS032949984; CCG-269834; CS-1115; DB15068; NSC-776043; NSC-800070; SB20796; NCGC00386234-02; NCGC00386234-03; AC-30297; AC013773; AS-74934; HY-15200; AC-013773; SW220118-1; A856125; Q27075853; 1-{3-[(6,7-DIMETHOXYQUINAZOLIN-4-YL)OXY]PHENYL}-3-[5-(1,1,1-TRIFLUORO-2-METHYLPROPAN-2-YL)-1,2-OXAZOL-3-YL]UREA; Urea, N-[3-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-3-isoxazolyl]-
    Click to Show/Hide
Structure
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
7
IsoSMILES
CC(C)(C1=CC(=NO1)NC(=O)NC2=CC(=CC=C2)OC3=NC=NC4=CC(=C(C=C43)OC)OC)C(F)(F)F
InChI
InChI=1S/C24H22F3N5O5/c1-23(2,24(25,26)27)19-11-20(32-37-19)31-22(33)30-13-6-5-7-14(8-13)36-21-15-9-17(34-3)18(35-4)10-16(15)28-12-29-21/h5-12H,1-4H3,(H2,30,31,32,33)
InChIKey
DKNUPRMJNUQNHR-UHFFFAOYSA-N
PubChem CID
56846693
INTEDE ID
DR00774
DrugBank ID
DB15068
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
Click to Show/Hide the Resistance Disease of This Class
Colon cancer [ICD-11: 2B90]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
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
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Agerafenib by aberration of the drug's therapeutic target
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
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
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Agerafenib by aberration of the drug's therapeutic target
Thyroid cancer [ICD-11: 2D10]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
 Disease Info 
Molecule Alteration Missense mutation
p.C634W (c.1902C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Inhibition hsa04210
AKT signaling pathway Inhibition hsa04151
In Vitro Model LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
TT cells Thyroid gland Homo sapiens (Human) CVCL_1774
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Phospho-protein profiling assay
Experiment for
Drug Resistance		 CellTiter-Glo assay
Mechanism Description RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLC gamma.
References
Ref 1 CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activityMol Cancer Ther. 2012 Apr;11(4):930-41. doi: 10.1158/1535-7163.MCT-11-0645. Epub 2012 Feb 7.
Ref 2 Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or MutationsClin Cancer Res. 2017 Jun 15;23(12):2981-2990. doi: 10.1158/1078-0432.CCR-16-1887. Epub 2016 Dec 23.

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