Drug Information

Drug (ID: DG01621) and It's Reported Resistant Information
Name
AGI-6780
Synonyms
AGI-6780; 1432660-47-3; AGI6780; N-cyclopropyl-4-(thiophen-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)benzenesulfonamide; AGI 6780; 1-[5-(Cyclopropylsulfamoyl)-2-Thiophen-3-Yl-Phenyl]-3-[3-(Trifluoromethyl)phenyl]urea; 1-[5-(CYCLOPROPYLSULFAMOYL)-2-(THIOPHEN-3-YL)PHENYL]-3-[3-(TRIFLUOROMETHYL)PHENYL]UREA; MLS006011046; CHEMBL3392845; SCHEMBL15702521; AOB2268; C21H18F3N3O3S2; DTXSID50744321; EX-A356; QCR-283; BDBM339679; HMS3653I21; HMS3744K17; HMS3865L13; BCP07383; 2198AH; FD5013; MFCD26097285; NSC781409; s7241; US10202339, Compound 124; ZINC95803998; AKOS024462890; CCG-269561; CS-1556; NSC-781409; SB19578; NCGC00347935-01; NCGC00347935-02; NCGC00347935-08; AS-55922; DA-35354; HY-15734; SMR004702838; FT-0764734; SW220033-1; Q27452174; S900006230; 1-[5-(cyclopropylsulfamoyl)-2-thiophen-3-ylphenyl]-3-[3-(trifluoromethyl)phenyl]urea; 3-(5-(cyclopropylsulfamoyl)-2-(thiophen-3-yl)phenyl)-1-(3-(trifluoromethyl)phenyl)urea; N-Cyclopropyl-3-[3-[3-(trifluoromethyl)phenyl]ureido]-4-(3-thienyl)benzenesulfonamide; 1K9; N-Cyclopropyl-4-(thiophen-3-yl)-3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)benzene-1-sulfonamide; N-Cyclopropyl-4-(thiophen-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)benzenesulfonamide
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Structure
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
6
IsoSMILES
C1CC1NS(=O)(=O)C2=CC(=C(C=C2)C3=CSC=C3)NC(=O)NC4=CC=CC(=C4)C(F)(F)F
InChI
InChI=1S/C21H18F3N3O3S2/c22-21(23,24)14-2-1-3-16(10-14)25-20(28)26-19-11-17(32(29,30)27-15-4-5-15)6-7-18(19)13-8-9-31-12-13/h1-3,6-12,15,27H,4-5H2,(H2,25,26,28)
InChIKey
CCAWRGNYALGPQH-UHFFFAOYSA-N
PubChem CID
71299339
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  MRAP: Metabolic Reprogramming via Altered Pathways
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
Acute myeloid leukemia [ICD-11: 2A60]
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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: Isocitrate dehydrogenase NADP 2 (IDH2) [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.R140Q (c.419G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5SVN
Mutant Type Structure Method: X-ray diffraction Resolution: 1.54  Å
PDB: 5I95
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.33
TM score: 0.99798
Amino acid change:
R140Q
 : 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 Blood N.A.
Mechanism Description The missense mutation p.R140Q (c.419G>A) in gene IDH2 cause the sensitivity of AGI-6780 by aberration of the drug's therapeutic target
Bladder cancer [ICD-11: 2C94]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [2]
Metabolic Type Glucose metabolism
Sensitive Disease Urothelial carcinoma [ICD-11: 2C94.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Adrenergic signaling in cardiomyocytes Activation hsa04261
In Vivo Model BALB/c-nu/nu mice, with UMUC3GR cells Mice
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.
References
Ref 1 Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiationScience. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769. Epub 2013 Apr 4.
Ref 2 IDH2 stabilizes HIF-1alpha-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. EMBO J. 2023 Feb 15;42(4):e110620.

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