Drug Information

Drug (ID: DG01483) and It's Reported Resistant Information
Name
U0126
Synonyms
U0126; 109511-58-2; U-0126; 1,4-Diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene; U 0126; UNII-8027P94HLL; CHEBI:64208; (2Z,3Z)-2,3-bis(amino((2-aminophenyl)thio)methylene)succinonitrile; 8027P94HLL; C18H16N6S2; (2Z,3Z)-bis{amino[(2-aminophenyl)sulfanyl]methylidene}butanedinitrile; 109511-58-2 (free); 218601-62-8; FT-1069-1; (2z)-Bis{amino[(2-Aminophenyl)sulfanyl]methylidene}butanedinitrile; (2Z,3Z)-bis{amino[(2-aminophenyl)sulfanyl]methylene}succinonitrile; 1,4-Diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene; (2Z,3Z)-2,3-bis[amino-(2-aminophenyl)sulfanylmethylidene]butanedinitrile; UO-126; BiomolKI_000002; BiomolKI2_000012; BMK1-B2; BSPBio_001224; CHEMBL34704; GTPL5282; Succinonitrile, bis(amino(o-aminophenylthio)methylene)-; CHEBI:90693; CHEBI:91463; Butanedinitrile, bis(amino((2-aminophenyl)thio)methylene)-; DTXSID10892034; HMS1362N05; HMS1792N05; HMS1990N05; HMS3403N05; HMS3414K05; HMS3678K05; AMY31125; BCP01851; EX-A1754; HY-12031A; (2Z,3Z)-2,3-bis[amino-(2-aminophenyl)sulfanyl-methylene]butanedinitrile; (2Z,3Z)-bis({amino[(2-aminophenyl)sulfanyl]methylidene})butanedinitrile; AKOS024456414; ZINC100007148; CCG-100606; LS40194; IDI1_002207; SMP2_000197; NCGC00025029-02; NCGC00025029-03; NCGC00025029-04; CS-0003351; U 126; V2422; A846574; A906530; SR-01000597365; J-002297; Q7863562; SR-01000597365-1; BRD-K18787491-001-04-5; BRD-K46419649-001-01-8; 2,3-Bis(amino((2-aminophenyl)thio)methylene)succinonitrile; Butanedinitrile,2,3-bis[amino[(2-aminophenyl)thio]methylene]-; (2Z,3Z)-2,3-Bis[amino[(2-aminophenyl)thio]methylene]butanedinitrile; Butanedinitrile, bis(amino((2-aminophenyl)thio)methylene)-, (2Z,3Z)-; 5BM
    Click to Show/Hide
Indication
In total 1 Indication(s)
Breast cancer [ICD-11: 2C60]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Melanoma [ICD-11: 2C30]
[2]
Target Estrogen receptor (ESR) ESR1_HUMAN [2]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
5
IsoSMILES
C1=CC=C(C(=C1)N)S/C(=C(/C(=C(/SC2=CC=CC=C2N)\\N)/C#N)\\C#N)/N
InChI
InChI=1S/C18H16N6S2/c19-9-11(17(23)25-15-7-3-1-5-13(15)21)12(10-20)18(24)26-16-8-4-2-6-14(16)22/h1-8H,21-24H2/b17-11+,18-12+
InChIKey
DVEXZJFMOKTQEZ-JYFOCSDGSA-N
PubChem CID
3006531
ChEBI ID
CHEBI:64208
TTD Drug ID
D04VFJ
Type(s) of Resistant Mechanism of This Drug
  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
Acute lymphocytic leukemia [ICD-11: 2B33]
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: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [1]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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L
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of U0126 by unusual activation of pro-survival pathway
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G469E (c.1406G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Human melanoma tissue N.A.
In Vivo Model (SCID) CB-17 mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.G469E (c.1406G>A) in gene BRAF cause the resistance of U0126 by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D594G (c.1781A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Human melanoma tissue N.A.
In Vivo Model (SCID) CB-17 mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.D594G (c.1781A>G) in gene BRAF cause the resistance of U0126 by unusual activation of pro-survival pathway
Uveal melanoma [ICD-11: 2D0Y]
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: Guanine nucleotide-binding protein alpha-q (GNAQ) [3]
Sensitive Disease Uveal melanoma [ICD-11: 2D0Y.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209L (c.626A>T)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.50  Å
PDB: 6VU5
Mutant Type Structure Method: Electron microscopy Resolution: 2.90  Å
PDB: 7F6G
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.91
TM score: 0.72705
Amino acid change:
Q209L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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260
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N
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270
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340
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K
K
D
D
T
T
I
I
L
L
350
|
Q
Q
L
L
N
N
L
L
K
K
E
E
Y
Y
N
N
L
L
V
V
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Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Eyeball N.A.
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 CyQUANT Cell (Invitrogen) proliferation assay
Mechanism Description The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of U0126 by unusual activation of pro-survival pathway
References
Ref 1 Shp2E76K mutant confers cytokine-independent survival of TF-1 myeloid cells by up-regulating Bcl-XLJ Biol Chem. 2007 Dec 14;282(50):36463-73. doi: 10.1074/jbc.M705789200. Epub 2007 Oct 17.
Ref 2 CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutationsOncogene. 2009 Jan 8;28(1):85-94. doi: 10.1038/onc.2008.362. Epub 2008 Sep 15.
Ref 3 Frequent somatic mutations of GNAQ in uveal melanoma and blue naeviNature. 2009 Jan 29;457(7229):599-602. doi: 10.1038/nature07586. Epub 2008 Dec 10.

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