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
  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]
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: Serine/threonine-protein kinase B-raf (BRAF) [2]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway
Breast cancer [ICD-11: 2C60]
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: Insulin-like growth factor 1 receptor (IGF1R) [3]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF7 cells Breast Homo sapiens (Human) CVCL_0031
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Cell cycle assay; Tissue microarrays staining assay
Mechanism Description MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance.
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) [4]
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) [4]
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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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
Key Molecule: Guanine nucleotide-binding protein alpha-q (GNAQ) [4]
Sensitive Disease Uveal melanoma [ICD-11: 2D0Y.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209P (c.626A>C)
 Molecule Info 
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.Q209P (c.626A>C) in gene GNAQ cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway
Peripheral nerve sheath tumor [ICD-11: 2F3Y]
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: Cyclin-dependent kinase 1 (CDK1) [1]
Resistant Disease Plexiform neurofibroma [ICD-11: 2F3Y.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model ipNF9511.bc cells Embryo Homo sapiens (Human) N.A.
ipNF05.5 cells Peripheral blood Homo sapiens (Human) CVCL_UI71
In Vivo Model NOD scid gamma mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RNA sequencing assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Cell cycle gene sets were significantly upregulated in both resistant cell lines, and specifically, resistant cell lines. That is, cell cycle gene sets were significantly upregulated in both resistant cell lines, and specifically, CDK1 gene activation was observed in both resistant cell lines.
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 BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitorsCancer Discov. 2012 Sep;2(9):791-7. doi: 10.1158/2159-8290.CD-12-0097. Epub 2012 Jul 13.
Ref 3 A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERalpha-positive luminal breast cancer. Biochem Pharmacol. 2022 Oct;204:115233.
Ref 4 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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