Drug Information
Drug (ID: DG01603) and It's Reported Resistant Information
Name |
Agerafenib
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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]-
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Structure | |||||
Target | . | NOUNIPROTAC | [1] | ||
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Formula |
7
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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
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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)
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InChIKey |
DKNUPRMJNUQNHR-UHFFFAOYSA-N
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PubChem CID | |||||
INTEDE ID | |||||
DrugBank ID |
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
Colon cancer [ICD-11: 2B90]
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) | [1] | |||
Molecule Alteration | Missense mutation | p.V600E (c.1799T>A) |
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Sensitive Disease | Colon cancer [ICD-11: 2B90.1] | |||
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]
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) | [1] | |||
Molecule Alteration | Missense mutation | p.V600E (c.1799T>A) |
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Sensitive Disease | Melanoma [ICD-11: 2C30.0] | |||
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]
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | ||||
Unusual Activation of Pro-survival Pathway (UAPP) | ||||
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) | [2] | |||
Molecule Alteration | Missense mutation | p.C634W (c.1902C>G) |
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Sensitive Disease | Thyroid gland cancer [ICD-11: 2D10.0] | |||
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 blotting 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
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