Drug Information

Drug (ID: DG01493) and It's Reported Resistant Information

• Name: Pyridone 6
• Synonyms: Pyridone 6; 457081-03-7; JAK Inhibitor I; Merck-5; CMP 6; Merck 5; CMP-6; 2-tert-butyl-9-fluoro-3H-benzo[h]imidazo[4,5-f]isoquinolin-7(6H)-one; LDX3F0CCST; UNII-LDX3F0CCST; CHEMBL21156; 2-(1,1-Dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinolin-7-one; CHEBI:87103; Compound # 2; 2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE; 2-(1,1-Dimethylethyl)-9-fluoro-1,6-dihydro-7H-benz[h]imidazo[4,5-f]isoquinolin-7-one; 2-TERT-BUTYL-9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLINE-7-ONE; C18H16FN3O; JAK Inhibitor; 2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one; 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one; JAK I inhibitor; Jak Inhibitor 1; PDK1 inhibitor, 1; Kinome_3740; pan-JAK inhibitor P6; 2b7a; Merck-5;CMP 6; Tetracyclic Pyridone, 1; JAK Inhibitor I(Merck 5); SCHEMBL904545; GTPL5992; STO185; SCHEMBL23199918; BDBM26198; DTXSID40420526; EX-A123; SYN1054; BCPP000167; HMS3229G07; HMS3244K21; HMS3244K22; HMS3244L21; BCP01959; Janus-Associated Kinase Inhibitor I; 3809AH; MFCD17019334; ZINC12504479; AKOS026750650; AKOS030240416; AKOS032949970; BCP9000906; CCG-206761; CS-1056; DB04716; SB18936; 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one; NCGC00345828-01; NCGC00345828-07; AM806646; AS-16211; HY-14435; QC-10171; FT-0700310; Y0239; H11177; K00013; K00225; SR-03000000978-1; Q27096425; 2-(tert-butyl)-9-fluoro-3H-benzo[h]imidazo[4,5-f]isoquinolin-7(6H)-one; 2-(1,1-dimethylethyl)-9-fluoro-3,6-dihydro-7h-benz [h]-imidazo [4,5-f]isoquinolin-7-one; 2-tert-butyl-9-fluoro-1,6-dihydro-7h-benz[h]imidazo[4,5-f]isoquinolin-7-one; 2-tert-butyl-9-fluoro-1,6-dihydro-7h-benzo[h]imidazo[4,5-f]isoquinolin-7-one; 4-tert-butyl-15-fluoro-3,5,10-triazatetracyclo[11.4.0.0(2),.0,(1)(2)]heptadeca-1(13),2(6),4,7(12),8,14,16-heptaen-11-one; 4-tert-butyl-15-fluoro-3,5,10-triazatetracyclo[11.4.0.0,.0,]heptadeca-1(13),2(6),4,7(12),8,14,16-heptaen-11-one; 4-tert-butyl-15-fluoro-3,5,10-triazatetracyclo[11.4.0.0^{2,6.0^{7,12]heptadeca-1(13),2(6),4,7(12),8,14,16-heptaen-11-one; 4-tert-butyl-15-fluoro-3,5,10-triazatetracyclo[11.4.0.0^{2,6}.0^{7,12}]heptadeca-1(13),2(6),3,7(12),8,14,16-heptaen-11-one; 4-tert-butyl-15-fluoro-3,5,10-triazatetracyclo[11.4.0.0^{2,6}.0^{7,12}]heptadeca-1(17),2(6),4,7(12),8,13,15-heptaen-11-one; 4-tert-butyl-15-fluoro-3,5,10-triazatetracyclo[11.4.0.02,6.07,12]heptadeca-1(13),2(6),4,7(12),8,14,16-heptaen-11-one; JAK Inhibitor I; 2-(1,1-Dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinolin-7-one
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Investigative; [1]
• Target: Bacterial Penicillin binding protein (Bact PBP); NOUNIPROTAC; [2]
• Formula: 1
• IsoSMILES: CC(C)(C)C1=NC2=C(N1)C3=C(C=C(C=C3)F)C4=C2C=CNC4=O
• InChI: InChI=1S/C18H16FN3O/c1-18(2,3)17-21-14-10-5-4-9(19)8-12(10)13-11(15(14)22-17)6-7-20-16(13)23/h4-8H,1-3H3,(H,20,23)(H,21,22)
• InChIKey: VNDWQCSOSCCWIP-UHFFFAOYSA-N
• PubChem CID: 5494425
• ChEBI ID: CHEBI:87103
• TTD Drug ID: D0PH5Z

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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 Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [3]

• Molecule Alteration: Missense mutation; p.R201L (c.602G>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human liver cancer tissue; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.R201L (c.602G>T) in gene GNAS cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Adenylate cyclase-stimulating G alpha protein (GNAS) [3]

• Molecule Alteration: Missense mutation; p.R201H (c.602G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human liver cancer tissue; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.R201H (c.602G>A) in gene GNAS cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

Myeloproliferative neoplasm [ICD-11: 2A22]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: E3 ubiquitin-protein ligase CBL (CBL) [2]

• Molecule Alteration: Missense mutation; p.C384R (c.1150T>C)
• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.C384R (c.1150T>C) in gene CBL cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Thrombopoietin receptor (TPOR) [1]

• Molecule Alteration: Missense mutation; p.W515F (c.1544_1545delGGinsTT)
• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• In Vivo Model: Balb/C donor mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: In vitro colony-forming assay
• Mechanism Description: The missense mutation p.W515F (c.1544_1545delGGinsTT) in gene MPL cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [4]

• Molecule Alteration: Missense mutation; p.Q501H (c.1503G>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.Q501H (c.1503G>T) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [4]

• Molecule Alteration: Missense mutation; p.R657Q (c.1970G>A)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.R657Q (c.1970G>A) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [4]

• Molecule Alteration: Missense mutation; p.I87T (c.260T>C)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.I87T (c.260T>C) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Lymphoma [ICD-11: 2A90- 2A85]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Molecule Alteration: Missense mutation; p.A572V (c.1715C>T)
• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NK-S1 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.A572V (c.1715C>T) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Molecule Alteration: Missense mutation; p.A573V (c.1718C>T)
• Sensitive Disease: Lymphoma [ICD-11: 2A90- 2A85]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NK-S1 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.A573V (c.1718C>T) in gene JAK3 cause the sensitivity of JAK inhibitors by aberration of the drug's therapeutic target

Breast cancer [ICD-11: 2C60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [6]

• Molecule Alteration: Copy number gain; .
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: HCC1954 cells; Breast; Homo sapiens (Human); CVCL_1259
• In Vitro Model: MDA-231 cells; Pleural effusion; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: SUM159PT cells; Breast; Homo sapiens (Human); CVCL_5423/CVCL_5590
• In Vitro Model: HCC38 cells; Breast; Homo sapiens (Human); CVCL_1267
• In Vitro Model: HCC1143 cells; Breast; Homo sapiens (Human); CVCL_1245
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SRB assay

References

• Ref 1: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasiaPLoS Med. 2006 Jul;3(7):e270. doi: 10.1371/journal.pmed.0030270.
• Ref 2: CBL linker region and RING finger mutations lead to enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via elevated levels of JAK2 and LYNJ Biol Chem. 2013 Jul 5;288(27):19459-70. doi: 10.1074/jbc.M113.475087. Epub 2013 May 21.
• Ref 3: GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activationJ Hepatol. 2012 Jan;56(1):184-91. doi: 10.1016/j.jhep.2011.07.018. Epub 2011 Aug 9.
• Ref 4: Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndromeBr J Haematol. 2008 May;141(5):681-8. doi: 10.1111/j.1365-2141.2008.07081.x. Epub 2008 Apr 7.
• Ref 5: Janus kinase 3-activating mutations identified in natural killer/T-cell lymphomaCancer Discov. 2012 Jul;2(7):591-7. doi: 10.1158/2159-8290.CD-12-0028. Epub 2012 Jun 15.
• Ref 6: Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependenceSci Transl Med. 2016 Apr 13;8(334):334ra53. doi: 10.1126/scitranslmed.aad3001.