Drug Information

Drug (ID: DG00635) and It's Reported Resistant Information
Name
TAK-733
Synonyms
TAK-733; 1035555-63-5; TAK733; TAK 733; (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione; UNII-5J61HSP0QJ; 5J61HSP0QJ; CHEMBL1615025; 3-[(2r)-2,3-Dihydroxypropyl]-6-Fluoro-5-[(2-Fluoro-4-Iodophenyl)amino]-8-Methylpyrido[2,3-D]pyrimidine-4,7(3h,8h)-Dione; Mek inhibitor tak-733; MLS006011054; GTPL9911; SCHEMBL1528606; DTXSID20648089; example 18 [US8470837]; AOB87182; BCP06625; EX-A2164; BDBM50337926; MFCD24386349; NSC761215; NSC800940; s2617; ZINC43196550; AKOS027251050; CCG-264969; CS-1283; DB12241; NSC-761215; NSC-800940; compound 17 [PMID: 21310613]; NCGC00263187-01; 3-[(2R)-2,3-Dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione; HY-13449; SMR004702846; SW220152-1; US8470837, 18; A857992; Q27262384; 3-[(2r)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methylpyrido [2,3-d]pyrimidine-4,7(3h,8h)-dione; IZG; Pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione,3-[(2R)-2,3-dihydroxy-propyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methyl-
    Click to Show/Hide
Indication
In total 1 Indication(s)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Peripheral nerve sheath tumor [ICD-11: 2F3Y]
[1]
Target MAPK/ERK kinase kinase (MAP3K) NOUNIPROTAC [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C17H15F2IN4O4
IsoSMILES
CN1C2=C(C(=C(C1=O)F)NC3=C(C=C(C=C3)I)F)C(=O)N(C=N2)C[C@H](CO)O
InChI
1S/C17H15F2IN4O4/c1-23-15-12(16(27)24(7-21-15)5-9(26)6-25)14(13(19)17(23)28)22-11-3-2-8(20)4-10(11)18/h2-4,7,9,22,25-26H,5-6H2,1H3/t9-/m1/s1
InChIKey
RCLQNICOARASSR-SECBINFHSA-N
PubChem CID
24963252
TTD Drug ID
D0I3RD
DrugBank ID
DB12241
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  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
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 subunit alpha-11 (GNA11) [2]
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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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Wn1366 cells Skin Homo sapiens (Human) CVCL_6789
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
SBCL2 cells Skin Homo sapiens (Human) CVCL_D732
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The missense mutation p.Q209L (c.626A>T) in gene GNA11 cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway
Key Molecule: Guanine nucleotide-binding protein alpha-q (GNAQ) [2]
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
-
-
M
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Y
Y
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240
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V
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E
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E
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R
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A
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260
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I
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D
D
K
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I
I
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Y
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C
A
A
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D
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340
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V
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F
A
A
A
A
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I
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Q
Q
L
L
N
N
L
L
K
K
E
E
Y
Y
N
N
L
L
V
V
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Wn1366 cells Skin Homo sapiens (Human) CVCL_6789
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
SBCL2 cells Skin Homo sapiens (Human) CVCL_D732
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway
References
Ref 1 Combined Cyclin-Dependent Kinase Inhibition Overcomes MAPK/Extracellular Signal-Regulated Kinase Kinase Inhibitor Resistance in Plexiform Neurofibroma of Neurofibromatosis Type I .J Invest Dermatol. 2022 Mar;142(3 Pt A):613-623.e7. doi: 10.1016/j.jid.2021.07.164. Epub 2021 Sep 15. 10.1016/j.jid.2021.07.164
Ref 2 Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell linesMol Cancer. 2012 Apr 19;11:22. doi: 10.1186/1476-4598-11-22.

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