Drug Information

Drug (ID: DG01908) and It's Reported Resistant Information
Name
DETD-35
Synonyms
DETD-35
    Click to Show/Hide
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
Melanoma [ICD-11: 2C30]
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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 Mutation
.
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375-R cells Skin Homo sapiens (Human) CVCL_6234
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Acquired resistance to?vemurafenib?(PLX4032) is a thorny issue in BRAFV600E?mutant?melanoma?therapy. Ferroptotic?programmed cell death?is a potential strategy for combating therapy-resistant cancers. This study uncovers the adaptation and abnormal upregulation of PUFAs and bioactive?oxylipin?metabolism in PLX4032 resistant melanoma cells. Phyto-sesquiterpene lactone, DET, and its derivative, DETD-35, induced?lipid?ROS?accumulation and triggered?ferroptotic cell death?in PLX4032 sensitive (A375) and resistant (A375-R) BRAFV600E?melanoma cells by reprogramming?glutathione?and primary metabolisms, lipid/oxylipin metabolism, and causing mitochondrial damage in which DETD-35 showed superior efficiency to DET.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]
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
Cell Pathway Regulation MEK/ERK signaling pathway Inhibition hsa04011
AKT signaling pathway Inhibition hsa04151
STAT3 signaling pathway Inhibition hsa04550
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
MeWo cells Skin Homo sapiens (Human) CVCL_0445
A2058 cells Skin Homo sapiens (Human) CVCL_1059
B16-F10 cells Skin Mus musculus (Mouse) CVCL_0159
SkMEL2 cells Skin Homo sapiens (Human) CVCL_0069
BRAF cells N.A. Homo sapiens (Human) N.A.
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Immunohistochemistry analysis
Experiment for
Drug Resistance		 MTT assay; Crystal violet staining assay; FACS assay
Mechanism Description DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells.
References
Ref 1 Phyto-sesquiterpene lactones DET and DETD-35 induce ferroptosis in vemurafenib sensitive and resistant melanoma via GPX4 inhibition and metabolic reprogramming. Pharmacol Res. 2022 Apr;178:106148.
Ref 2 A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in MiceMol Cancer Ther. 2016 Jun;15(6):1163-76. doi: 10.1158/1535-7163.MCT-15-0973. Epub 2016 Apr 5.

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