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-
• Indication:
  In total 1 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Investigative; [1]
• 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]
• 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

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blotting 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]

• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blotting 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

Uveal melanoma [ICD-11: 2D0Y]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [3]

• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Wn1366 cells; Skin; Homo sapiens (Human); CVCL_6789
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: SBCL2 cells; Skin; Homo sapiens (Human); CVCL_D732
• Experiment for Molecule Alteration: Western blotting 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) [3]

• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Wn1366 cells; Skin; Homo sapiens (Human); CVCL_6789
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: SBCL2 cells; Skin; Homo sapiens (Human); CVCL_D732
• Experiment for Molecule Alteration: Western blotting 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

Key Molecule: Guanine nucleotide-binding protein alpha-q (GNAQ) [3]

• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Wn1366 cells; Skin; Homo sapiens (Human); CVCL_6789
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: SBCL2 cells; Skin; Homo sapiens (Human); CVCL_D732
• Experiment for Molecule Alteration: Western blotting 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

Peripheral nerve sheath tumor [ICD-11: 2F3Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase 1 (CDK1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Plexiform neurofibroma [ICD-11: 2F3Y.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: ipNF9511.bc cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: 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: 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.