Drug Information

Drug (ID: DG01618) and It's Reported Resistant Information

• Name: GSK126
• Synonyms: GSK126; 1346574-57-9; GSK-126; GSK 126; GSK2816126; (S)-1-(sec-Butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide; EZH2 inhibitor; UNII-W4OGW9QZ97; GSK-2816126; W4OGW9QZ97; CHEMBL3287735; 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide; 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-(6-piperazin-1-ylpyridin-3-yl)indole-4-carboxamide; A9G; N-((1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-3-methyl-1-((1S)-1-methylpropyl)-6-(6-(1-piperazinyl)-3-pyridinyl)-1H-indole-4-carboxamide; N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide; GSK126 HCl; GSK-126 HCl; MLS006010251; GTPL7012; SCHEMBL12180401; AOB1764; EX-A499; SYN5012; CHEBI:124921; BCP06129; BDBM50017293; GSK-2816126A; NSC780041; NSC789702; s7061; ZINC72318146; AKOS027322309; CCG-269895; CS-1401; NSC-780041; NSC-789702; QC-9703; NCGC00347286-01; 1H-Indole-4-carboxamide, N-((1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-3-methyl-1-((1S)-1-methylpropyl)-6-(6-(1-piperazinyl)-3-pyridinyl)-; AS-16379; HY-13470; SMR004701327; X5824; Q27077865; EZH2 inhibitor;GSK-126;GSK 126;GSK2816126A;GSK-2816126A;GSK 2816126A; (S)-1-sec-butyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide; N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide
• Indication:
  In total 4 Indication(s)
  Anaplastic large cell lymphoma [ICD-11: 2A90]; Phase 1; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Phase 1; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Phase 1; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Phase 1; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Diffuse large B-cell lymphoma [ICD-11: 2A81]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
• Target: ALK tyrosine kinase receptor (ALK); ALK_HUMAN; [3]
• Formula: 7
• IsoSMILES: CC[C@H](C)N1C=C(C2=C(C=C(C=C21)C3=CN=C(C=C3)N4CCNCC4)C(=O)NCC5=C(C=C(NC5=O)C)C)C
• InChI: InChI=1S/C31H38N6O2/c1-6-22(5)37-18-20(3)29-25(30(38)34-17-26-19(2)13-21(4)35-31(26)39)14-24(15-27(29)37)23-7-8-28(33-16-23)36-11-9-32-10-12-36/h7-8,13-16,18,22,32H,6,9-12,17H2,1-5H3,(H,34,38)(H,35,39)/t22-/m0/s1
• InChIKey: FKSFKBQGSFSOSM-QFIPXVFZSA-N
• PubChem CID: 68210102
• ChEBI ID: CHEBI:124921
• TTD Drug ID: D08PIE

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [2]

• Molecule Alteration: Missense mutation; p.Y111D (c.331T>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Pfeiffer cells; Pleural effusion; Homo sapiens (Human); CVCL_3326
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Diffuse large B-cell lymphoma [ICD-11: 2A81]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [1]

• Molecule Alteration: Missense mutation; p.Y641S (c.1922A>C)
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Chromatin Immunoprecipitation assay; Western blotting analysis
• Experiment for Drug Resistance: Propidium-iodide cell cycle analysis; BrdU-PI cell cycle analysis

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]

• Molecule Alteration: Missense mutation; p.Y641S (c.1922A>C)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; BCA assay
• Mechanism Description: EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]

• Molecule Alteration: Missense mutation; p.Y641N (c.1921T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; BCA assay
• Mechanism Description: EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]

• Molecule Alteration: Missense mutation; p.Y641H (c.1921T>C)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.
• Experiment for Molecule Alteration: Western blotting analysis; BCA assay
• Mechanism Description: EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [3]

• Molecule Alteration: Missense mutation; p.Y646N (c.1936T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKMEL-28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: MM386 cells; Lymph node; Homo sapiens (Human); CVCL_2607
• In Vitro Model: MM200 cells; Skin; Homo sapiens (Human); CVCL_C836
• In Vitro Model: MEL-RM cells; Lymph node; Homo sapiens (Human); CVCL_D548
• In Vitro Model: MEL-JD cells; Lymph node; Homo sapiens (Human); CVCL_BS80
• In Vitro Model: ME4405 cells; Skin; Homo sapiens (Human); CVCL_C680
• In Vitro Model: ME1007 cells; Skin; Homo sapiens (Human); CVCL_C668
• In Vitro Model: IGR1 Mel-RMU cells; Lymph node; Homo sapiens (Human); CVCL_S994
• In Vitro Model: HEM cells; N.A.; .; N.A.
• In Vitro Model: HDF cells; N.A.; .; N.A.
• In Vitro Model: C001 cells; Skin; Homo sapiens (Human); CVCL_B4K8
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [3]

• Molecule Alteration: Missense mutation; p.Y646N (c.1936T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKMEL-28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: MM386 cells; Lymph node; Homo sapiens (Human); CVCL_2607
• In Vitro Model: MM200 cells; Skin; Homo sapiens (Human); CVCL_C836
• In Vitro Model: MEL-RM cells; Lymph node; Homo sapiens (Human); CVCL_D548
• In Vitro Model: MEL-JD cells; Lymph node; Homo sapiens (Human); CVCL_BS80
• In Vitro Model: ME4405 cells; Skin; Homo sapiens (Human); CVCL_C680
• In Vitro Model: ME1007 cells; Skin; Homo sapiens (Human); CVCL_C668
• In Vitro Model: IGR1 Mel-RMU cells; Lymph node; Homo sapiens (Human); CVCL_S994
• In Vitro Model: HEM cells; N.A.; .; N.A.
• In Vitro Model: HDF cells; N.A.; .; N.A.
• In Vitro Model: C001 cells; Skin; Homo sapiens (Human); CVCL_B4K8
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

References

• Ref 1: HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphomaOncotarget. 2015 Mar 10;6(7):4863-87. doi: 10.18632/oncotarget.3120.
• Ref 2: Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitorsOncotarget. 2015 Oct 20;6(32):32646-55. doi: 10.18632/oncotarget.5066.
• Ref 3: Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genesOncotarget. 2015 Sep 29;6(29):27023-36. doi: 10.18632/oncotarget.4809.
• Ref 4: Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in MelanomaNeoplasia. 2016 Feb;18(2):121-32. doi: 10.1016/j.neo.2016.01.003.