ES2522830T3 - Métodos de control de la eficacia de los inhibidores de la farnesiltransferasa - Google Patents

Métodos de control de la eficacia de los inhibidores de la farnesiltransferasa Download PDF

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ES2522830T3
ES2522830T3 ES11158145.0T ES11158145T ES2522830T3 ES 2522830 T3 ES2522830 T3 ES 2522830T3 ES 11158145 T ES11158145 T ES 11158145T ES 2522830 T3 ES2522830 T3 ES 2522830T3
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Anne Fourie
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Janssen Pharmaceutica NV
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Abstract

Un método para determinar una respuesta de un sujeto que padece sepsis o shock séptico al tratamiento con un inhibidor de la farnesil transferasa, que comprende las etapas: (i) medir un nivel de al menos un marcador seleccionado entre el grupo que consiste en proteínas identificadas en la Tabla 4 y en los transcriptos de los genes identificados en las Tablas 2 y 3 en una muestra de sangre sin tratar obtenida del sujeto antes del tratamiento con el inhibidor de la farnesil transferasa, y (ii) medir un nivel del marcador en una muestra de sangre tratada obtenida del sujeto al menos una vez después del comienzo del tratamiento con el inhibidor de la farnesil transferasa, y (iii) comparar dichos nivel del marcador, donde una disminución del nivel del marcador medido en la muestra de sangre sin tratar con el nivel del marcador medido en la muestra de sangre tratada indica una respuesta al tratamiento.

Description

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inhibición de farnesil) después del que LPS (o el vehículo sólo sin tratamiento) se añadió a una concentración final de 10 ng/ml. Se recogieron los sobrenadantes a las 16 horas, 24 horas y 40 horas de tratamiento con LPS, y la secreción de IL-6 se cuantificó por ELISA. La importancia estadística para las diferencias en la producción de IL-6 en tipifarnib-versus PBMC tratado con vehículo se evaluó mediante la prueba t de Student. Las diferencias
5 estadísticamente significativas se indican con asteriscos ** significa valor medio de P inferior a 0,01. Cuanto menor sea el valor de P, más significativa es la diferencia.
La Figura 7a – 7b muestra el efecto de tipifarnib en LPS, TNF – α, y la señalización inducida por IL – 1. Las células THP – 1 se cultivaron en ausencia o presencia de 2 µM de tipifarnib durante 18 horas, a continuación se incubaron con LPS y TNF – α (Figura 7.a), o LPS, TNF – α eIL -1α (Figura 7.b) durante 30 minutos. Los lisados celulares se analizaron por inmunoelectrotransferencia, utilizando anticuerpos contra p38, p38 fosforilado, fosfo – ERK 1 / 2, IκB, y H – Ras.
La Figura 8 muestra que tipifarnib no inhibe la expresión del gen reportero dependiente de NF – κB inducida por
15 TNF – α. Las células HEK293 transfectadas en κB – LH se incubaron en ausencia o presencia de 2 y 5 µM de tipifarnib durante 18 horas, a continuación se estimularon con TNF – α durante 4 horas. La actividad de la luciferasa se midió y se expresó como un cambio múltiplo en presencia de TNF – α contra ningún TNF – α, o TNF – α / tipifarnib contra tipifarnib. Los valores se presentan como un factor de aumento ± D. E.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN Y REALIZACIONES PREFERIDAS
[0030] Los términos "que comprende", "que incluye" y "que contiene" se utiliza aquí en su sentido amplio, no limitado.
25 [0031] Los efectos biológicos de los FTI ahora se han elucidado aún más, como se discute en la sección Experimentos a continuación. La inhibición de la farnesil transferasa (FPTasa) se ha descubierto para regular a la baja los genes y proteínas identificadas en las Tablas 2, 3 y 4. Así, los niveles de dichos genes y proteínas pueden ser monitoreadas como marcadores biológicos para determinar la respuesta de un paciente al tratamiento con un FTI. Por ejemplo, diversos subconjuntos de genes y/o proteínas inducidos por LPS que se muestran en las tablas siguientes pueden ser regulados a la baja por la administración de un inhibidor de farnesiltransferasa y por lo tanto utilizarse como marcadores en los estudios clínicos.
Tabla 2: Genes para los que la transcripción inducida por LPS fue regulada a la baja por la inhibición de
farnesiltransferasa, según lo medido por el análisis de microarrays de ADNc
35
45
55
65
Número de registro
Nombre del gen Descripción del gen
NM_002982
CCL2 proteína quimiotáctica de monocitos 1 (MCP-1)
NM_005623
CCL8 proteína quimiotáctica de monocitos 2 (MCP-2)
NM_002983
CCL3 citoquina A3 pequeña inducible (homóloga de Mip-1a de ratón) (SCYA3)
NM_002984
CCL4 citoquina A4 pequeña inducible (homóloga de MiP-1b de ratón) (SCYA4)
NM_005409
CXCL11 subfamilia B de citoquina pequeña inducible (SCYB11)
NM_000576
IL1B interleucina 1, beta
MM_000577
IL1RN interleucina-1 antagonista del receptor
MM_002852
PTX3 gen relacionado de pentaxina, rápidamente inducido por IL-1B
NM_007315
STAT1 transductor de señales y activador de transcripción 1
NM_002176
IFNB1 interferón, beta 1, fibroblastos
NM_005531
IFI16 interferón, proteína 16 inducible por gamma
13
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5
15
25
35
45
55
NM_001548
IFIT1 proteína inducida por interferón con repeticiones tetratricopeptidas 1
MM_002462
MX1 mixovirus (influenza) resistencia 1
NM_000598
IGFBP3 Gen de proteína-3 de unión de factor de crecimiento a modo de insulina
NM_053056
CCND1 ciclina D1 (PRAD1: adenomatosis paratiroidea 1)
NM_002965
S100A9 S100 calcio-proteína de unión A9 (calgranulina B)
NM_002468
MYD88 proteína de respuesta primaria de diferenciación mieloide
NM_000593
TAP1 transportador 1, cassette ATP de unión, subfamilia B (MDR / TAP)
MM_000544
TAP2 transportador 2, cassette ATP de unión, subfamilia B (MDR / TAP)
NM_007188
ABCB8 cassette ATP de unión, subfamilia B (MDR / TAP), miembro 8
NM_031460
KCNK17 potassium channel, subfamily K, member 17 (TASK-4)
NM_002659
PLAUR plasminogen activator, urokinase receptor
NM_004054
C3AR1 C3a anaphylatoxin chemotactic receptor (C3a-R)
NM_004048
B2M beta-2-microglobulin
MM_015907
LAP3 leucine aminopeptidase
NM_004994
MMP9 type IV collagenase, matrix metalloproteinase 9
NM_006074
TRIM22 tripartite motif-containing 22
MM_144573
NEXN nexilin (F actin binding protein)
NM_021634
LGR7 leucine-rich repeat-containing G proteincoupled receptor 7
NM_198066
GNPNAT1 glucosamine-phosphate Nacetyltransferase 1
No_002346
LY6E lymphocyte antigen 6 complex, locus E
14
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NM_001548
IFIT1 interferon-induced protein with tetratricopeptide repeats 1
NM_002462
MX1 myxovirus (influenza) resistance 1
NM_000598
IGFBP3 insulin-like growth factor-binding protein-3 gene
NM_053056
CCND1 cyclin D1 (PRAD1: parathyroid adenomatosis 1)
NM_002965
S100A9 S100 calcium-binding protein A9 (calgranulin B)
NM_003897
IER3 immediate early response 3
MM_002468
MYD88 myleoid differentiation primary response protein
NM_002502
NFKB2 nuclear factor of kappa light polypeptide gene enhancer in B-cells 2
NM_000593
TAP1 transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
NM_000544
TAP2 transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)
NM_007188
ABCB8 ATP-binding cassette, sub-family B (MDR/TAP), member 8
NM 031460
KCNK17 potassium channel, subfamily K, member 17 (TASK-4)
NM_002659
PLAUR plasminogen activator, urokinase receptor
NM_004054
C3AR1 C3a anaphylatoxin chemotactic receptor (C3a-R)
NM_004048
B2M beta-2-microqlobulin
NM_015907
LAP3 leucine aminopeptidase
NM_004994
MMP9 type IV collagenase, matrix metalloproteinase 9
NM_000362
TIMP3 tissue inhibitor of metalloproteinase 3
NM_006074
TRIM22 tripartite motif-containing 22
NM_004223
UBE2L6 ubiquitin-conjugating enzyme E2L 6
NM_144573
NEXN nexilin (F actin binding protein)
NM_021634
LGR7 leucine-rich repeat-containing G protein-coupled receptor 7
NM_198066
GNPNAT1 glucosamine-phosphate N-acetyltransferase 1
NM_002346
LY6E lymphocyte antigen 6 complex, locus E
Tabla 1.b
Número de acceso
Nombre gen Factor de cambio (LPS vs control)
1hr
3hr 6hr 2hr 24hr
NM_002982
CCL2 1.00 1.41 9.8 9.85 21.11
NM_005623
CCL8 1.00 1.00 3.48 2.30 3.7
NM_002983
CCL3 1.32 4.92 6.06 4.29 7.46
NM_002984
CCL4 1.32 5.28 8.00 5.66 6.96
NM_005409
CXCL11 1.00 1.15 7.46 3.03 2.30
NM_000584
IL8 1.41 8.00 6.06 22.63 22.63
NM_000576
IL1B 1.41 5.66 8.00 6.96 8.00
NM_000577
IL1RN 1.07 1.00 3.25 1.87 4.29
NM_002852
PTX3 -1.07 2.00 4.00 3.03 3.48
NM_007315
STAT1 -1.23 1.15 4.29 3.73 4.29
NM_002176
IFNB1 1.07 1.23 3.25 6.06 1.87
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NM_005531
IF116 -1.07 1.00 1.74 2.00 2.83
NM_001548
IFIT1 1.00 1.07 2.83 2.83 3.03
NM_002462
MX1 1.00 1.07 4.92 3.03 3.25
NM_000598
IGFBP3 1.00 1.15 1.62 4.00 7.46
NM_053056
CCND1 1.00 1.07 1.23 1.74 2.00
NM_002965
S100A9 -1.07 -1.07 1.00 1.52 1.74
NM_003897
IER3 1.23 1.41 1.87 2.00 2.14
NM_002468
MYD88 1.00 1.07 3.25 1.74 1.74
NM_002502
NFKB2 1.07 1.41 2.83 2.46 1.52
NM_000593
TAP1 1.23 1.32 4.92 2.14 1.74
NM_000544
TAP2 1.07 1.07 2.00 1.87 1.41
NM_007188
ABCB8 1.00 1.00 2.30 1.52 1.52
NM_031460
KCNK17 1.07 1.23 3.03 1.52 2.00
NM_002659
PLAUR -1.07 1.15 1.62 1.87 3.25
NM_004054
C3AR1 -1.07 1.15 2.00 2.30 3.48
NM_004048
B2M -1.07 1.07 1.62 1.52 2.14
NM_015907
LAP3 -1.07 1.00 2.46 2.30 4.00
NM_004994
MMP9 -1.07 -1.07 1.52 3.48 13.93
NM_000362
TIMP3 NA NA 2.46 -1.41 -2.00
NM_006074
TRIM22 1.00 1.00 2.83 3.03 2.83
NM_004223
UBE2L6 1.00 -1.07 5.28 5.28 4.59
NM_144573
NEXN 1.00 1.00 2.00 1.52 1.52
NM_021634
LGR7 1.07 -1.07 1.62 1.52 1.87
NM_198066
GNPNAT1 1.00 1.00 3.25 2.14 1.74
NM_002346
LY6E 1.15 1.00 3.03 3.73 5.28
Tabla 1.c
Número de acceso
Nombre Gen Factor de cambio (simvastatin/LPS vs LPS)
1hr
3hr 6hr 12hr 24hr
NM_002982
CCL2 1.00 -1.23 -1.62 -2.14 NA
NM_005623
CCL8 -1.07 -1.07 -1.32 -1.52 -1.23
NM_002983
CCL3 1.15 1.00 -1.62 -1.15 1.41
NM_002984
CCL4 -1.07 1.74 -1.32 -1.15 1.41
NM_005409
CXCL11 1.00 1.00 -1.15 1.32 -1.32
NM_000584
IL8 -1.15 -1.23 -1.07 -1.74 1.23
NM_000576
IL1B 1.00 -1.15 -1.62 -2.14 -2.00
NM_000577
IL1RN -1.15 -1.07 -1.15 -1.07 -1.62
NM_002852
PTX3 -1.07 -1.07 -1.07 -1.23 1.23
NM_007315
STAT1 1.07 1.07 -1.32 1.07 -1.52
NM_002176
IFNB1 -1.15 -1.15 1.23 -1.87 -1.23
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NM_005531
IFI16 1.00 1.00 1.00 -1.07 -1.32
NM_001548
IFIT1 1.00 1.00 1.00 -1.07 -1.15
NM_002462
MX1 1.00 1.07 -1.15 1.23 -1.41
NM_000598
IGFBP3 1.00 1.07 1.00 1.15 1.07
NM_053056
CCND1 -1.07 1.00 -1.07 -1.62 -1.52
NM_002965
S100A9 -1.07 -1.07 -1.07 -1.32 1.41
NM_003897
IER3 1.00 1.00 -1.23 -1.62 1.23
NM_002468
MYD88 1.07 1.07 -1.07 1.00 1.00
NM_002502
NFKB2 -1.07 1.00 -1.74 -1.07 1.41
NM_000593
TAP1 -1.07 1.15 -1.41 1.00 1.15
NM_000544
TAP2 1.00 1.00 -1.23 1.00 -1.15
NM_007188
ABCB8 1.00 1.07 1.00 1.00 -1.07
NM_031460
KCNK17 1.00 1.00 1.07 1.00 -1.32
NM_002659
PLAUR 1.00 -1.15 -1.23 -1.87 -1.41
NM_004054
C3AR1 -1.15 1.00 1.00 -1.32 1.32
NM_004048
B2M 1.07 1.00 1.07 -1.07 1.00
NM_015907
LAP3 1.00 1.00 1.15 1.07 -1.52
NM_004994
MMP9 1.00 1.00 -1.15 -1.32 -2.14
NM_000362
TIMP3 NA NA -2.64 -1.07 -1.07
NM_006074
TRIM22 1.00 1.07 1.07 1.07 -1.15
NM_004223
UBE2L6 -1.07 1.00 1.00 1.15 -1.62
NM_144573
NEXN -1.07 1.07 -1.07 1.15 -1.32
NM_021634
LGR7 1.07 1.15 -1.07 -1.41 -1.32
NM_198066
GNPNAT1 1.00 1.00 -1.07 1.15 -1.23
NM_002346
LY6E 1.15 1.00 -1.07 1.52 -1.15
Tabla 1.d
Número de acceso
Nombre Gen Factor de cambio (tipifarnib/LPS vs LPS)
1hr
3hr 6hr 12hr 24hr
NM_002982
CCL2 -1.07 -1.32 -2.83 -3.25 -4.29
NM_005623
CCL8 -1.07 1.00 -2.30 -2.30 -3.48
NM_002983
CCL3 -1.07 1.00 -1.07 1.23 -1.52
NM_002984
CCL4 1.07 1.87 1.07 -1.52 -1.52
NM_005409
CXCL11 1.00 -1.07 -2.83 -1.52 -2.00
NM_000584
IL8 -1.07 -1.23 -1.15 1.32 -1.07
NM 000576
IL1B 1.07 1.32 -1.87 -2.46 -1.23
NM_000577
IL1RN -1.15 -1.15 -1.62 -1.15 -3.73
NM_002852
PTX3 1.15 -1.15 -1.32 -1.32 -2.00
NM_007315
STAT1 1.23 -1.32 -2.14 1.00 -1.62
NM_002176
IFNB1 -1.23 -1.15 -1.62 -3.03 2.14
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NM_005531
IFI16 1.07 1.00 -1.32 -1.23 -1.74
NM_001548
IFIT1 1.00 1.00 -1.41 -1.32 -2.1
NM_002462
MX1 1.00 -1.07 -1.74 1.32 -1.32
NM_000598
IGFBP3 1.00 -1.07 1.00 -1.52 -2.00
NM_053056
CCND1 1.00 -1.07 -1.15 -1.62 -1.23
NM_002965
S100A9 1.00 -1.15 -1.07 -2.00 -1.62
NM_003897
IER3 1.32 1.52 1.15 1.00 1.23
NM_002468
MYD88 1.07 -1.15 -2.14 -1.23 -1.32
NM_002502
NFKB2 -1.07 1.23 -1.07 -1.32 1.52
NM_000593
TAP1 -1.23 1.15 -1.74 -1.15 -1.23
NM_000544
TAP2 1.07 -1.15 -1.62 -1.32 -1.23
NM_007188
ABCB8 1.07 1.00 -1.62 -1.23 -1.23
NM_031460
KCNK17 -1.07 -1.15 -1.32 1.00 -1.74
NM_002659
PLAUR 1.00 -1.23 -1.62 -1.87 -1.62
NM_004054
C3AR1 1.00 1.07 -1.23 -1.6 -1.74
NM_004048
B2M 1.15 1.00 -1.23 -1.62 1.15
NM_015907
LAP3 -1.07 -1.07 -1.62 -1.23 -2.83
NM_004994
MMP9 -1.07 -1.07 -1.41 -1.74 -1.41
NM_000362
TIMP3 NA -1.41 -1.23 -1.15 1.15
NM_006074
TRIM22 1.00 1.00 -1.62 -1.07 -1.52
NM_004223
UBE2L6 1.00 -1.07 -1.41 -1.15 -1.41
NM_144573
NEXN 1.00 1.00 -1.41 -1.15 -1.62
NM_021634
LGR7 1.23 -1.15 -1.41 -1.62 -1.52
NM_198066
GNPNAT1 1.00 1.00 -2.00 -1.41 -1.74
NM_002346
LY6E 1.52 -1.15 -1.52 1.15 -1.32
[0109] Las Tablas 1a, 1b, 1c y 1d muestran los genes inducida por LPS que fueron inhibidos por la simvastatina o tipifarnib. Los genes fueron seleccionados (véase Tabla 1A para la descripción de genes) como LPS inducido si la relación entre LPS tratados y no tratados con muestras fue mayor que 1,5-veces en más de dos puntos de tiempo. 5 Estos se muestran como números en negrita cursiva en el "factor de cambio (LPS versus control)" de la columna (Tabla 1.b). La expresión génica durante el tratamiento con LPS y la estatina (simvastatina / LPS) (Tabla 1.c), o LPS y la IVR (tipifarnib / LPS) (Tabla 1.d), se comparó con el LPS solo en puntos de tiempo correspondientes. Genes que mostraron al menos 1,5 veces la disminución en la inducción por uno o ambos fármacos, en uno o más puntos de tiempo fueron seleccionados para su inclusión en la tabla. Los genes para el que se inhibe la inducción LPS de
10 acuerdo con estos criterios se muestran como números negativos, negrita y cursiva.
[0110] Los resultados del análisis de microarrays se confirmó por los genes seleccionados por análisis en tiempo real PCR (Figura 2). La transcripción de IL-1 p fue inducida por LPS tan pronto como 3 horas, y la inducción no se vio afectada por la simvastatina o tipifarnib hasta este punto de tiempo. Sin embargo, después de 6 horas, y en 15 mayor medida, después de 12 horas de la inducción inducida por LPS significativamente downregulated de simvastatina y tipifarnib (Figura 2.a). MCP-1 fue inducida por LPS a partir de 6 horas, y esta inducción fue inhibida significativamente por la simvastatina y tipifarnib (Figura 2.b). MMP-9 inducción por LPS aumentó hasta 12 horas, en cuyo tiempo del punto de una disminución del 50% en la inducción se observó para la simvastatina y la no inducción en presencia de tipifarnib (figura 2.c). La inducción de IL-8 por LPS fue evidente tan pronto como 3 horas y no fue 20 afectada por los fármacos en este punto de tiempo. A las 6 y 12 horas, la inducción de IL-8 fue inhibida por la simvastatina, mientras que la FTI no mostró ningún efecto significativo (figura 2.d). STAT1 inducción fue inhibida por tipifarnib a las 6 y 12 horas, mientras que la inhibición por la estatina sólo se observó a las 12 horas (figura 2.e). Factor de diferenciación mieloide, MyD88, el adaptador de tipo Toll respuestas mediadas por el receptor, se upregulated significativamente por LPS a 6 y 12 horas, y esto fue ligeramente inhibida por la simvastatina en 1225 horas (Figura 2.f). En contraste, tipifarnib mostraron una inhibición casi completa de MyD88 inducción, a niveles
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Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007529555A (ja) * 2004-03-18 2007-10-25 ザ ブライハム アンド ウイメンズ ホスピタル， インコーポレイテッド シヌクレイノパチーを治療する方法
US20060106060A1 (en) * 2004-03-18 2006-05-18 The Brigham And Women's Hospital, Inc. Methods for the treatment of synucleinopathies (Lansbury)
US20070293539A1 (en) * 2004-03-18 2007-12-20 Lansbury Peter T Methods for the treatment of synucleinopathies
EP1744751A4 (en) * 2004-03-18 2010-03-10 Brigham & Womens Hospital METHOD FOR THE TREATMENT OF SYNUCLEINOPATHIES
US8232402B2 (en) * 2008-03-12 2012-07-31 Link Medicine Corporation Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications
US20100160372A1 (en) * 2008-11-13 2010-06-24 Link Medicine Corporation Treatment of proteinopathies using a farnesyl transferase inhibitor
US20100331363A1 (en) * 2008-11-13 2010-12-30 Link Medicine Corporation Treatment of mitochondrial disorders using a farnesyl transferase inhibitor
US20110060005A1 (en) * 2008-11-13 2011-03-10 Link Medicine Corporation Treatment of mitochondrial disorders using a farnesyl transferase inhibitor
MX2011005096A (es) * 2008-11-13 2011-11-18 Link Medicine Corp Derivados de azaquinolinona y usos de los mismos.
CN104884448A (zh) 2012-10-16 2015-09-02 詹森药业有限公司 Rorγt的杂芳基连接的喹啉基调节剂
US9309222B2 (en) 2012-10-16 2016-04-12 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
JP6466335B2 (ja) 2012-10-16 2019-02-06 ヤンセン ファーマシューティカ エヌ．ベー． ＲＯＲ−γ−Ｔのメチレン連結キノリニルモジュレーター
CN105873439A (zh) 2013-10-15 2016-08-17 詹森药业有限公司 RORγt的烷基连接的喹啉基调节剂
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
KR20160068956A (ko) 2013-10-15 2016-06-15 얀센 파마슈티카 엔.브이. RORyT의 퀴놀리닐 조절제
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
US11311519B2 (en) 2014-05-01 2022-04-26 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US10076512B2 (en) 2014-05-01 2018-09-18 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
AU2015283811A1 (en) * 2014-07-02 2017-02-09 Bionomics Limited Predictive biomarkers
EP3226973A4 (en) * 2014-12-04 2018-05-30 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US10835496B2 (en) 2015-04-21 2020-11-17 Eiger Biopharmaceuticals, Inc. Pharmaceutical compositions comprising lonafarnib and ritonavir
EA201890512A1 (ru) 2015-08-17 2018-09-28 Кура Онколоджи, Инк. Способы лечения пациентов со злокачественными опухолями с использованием ингибиторов фарнезилтрансферазы
CN105510187B (zh) * 2016-01-28 2018-01-23 青岛啤酒股份有限公司 用于啤酒糖化过程中快速判定麦汁发酵度的方法
RS61745B1 (sr) 2016-11-03 2021-05-31 Kura Oncology Inc Inhibitori farneziltransferaze za upotrebu u tretiranju kancera
EP4136076A1 (en) * 2020-04-16 2023-02-22 F. Hoffmann-La Roche AG Biphenyl derivatives
US20250049837A1 (en) * 2023-01-09 2025-02-13 Unity Health Toronto Microrna-based particle for the treatment of dysregulated immune response
WO2025101692A1 (en) * 2023-11-10 2025-05-15 The Children's Medical Center Corporation Methods and compositions for the treatment of vascular anomalies

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5686472A (en) 1992-10-29 1997-11-11 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6117432A (en) 1995-04-20 2000-09-12 Societe D'exploitation De Produits Pour Les Industries Chimiques (S.E.P.P.I.C.) Therapeutic composition comprising an antigen or an in vivo generator of a compound comprising an amino acid sequence
TW349948B (en) 1995-10-31 1999-01-11 Janssen Pharmaceutica Nv Farnesyl transferase inhibiting 2-quinolone derivatives
EE03484B1 (et) 1995-12-08 2001-08-15 Janssen Pharmaceutica N.V. Farnesüülproteiintransferaasi inhibeerivad (5-imidasolüül)metüül-2-kinolinooni derivaadid ja nende kasutamine
US5874442A (en) 1995-12-22 1999-02-23 Schering-Plough Corporation Tricyclic amides useful for inhibition of G-protein function and for treatment of proliferative disease
US6011029A (en) 1996-02-26 2000-01-04 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
ATE252104T1 (de) 1996-12-20 2003-11-15 Tovarischestvo S Ogranichennoi Verfahren und gerät zur herstellung von 1ss, 10ss-epoxy-13-dimethylamino-guaia-3(4)-en-6,12- lid- hydrochlorid
TW591030B (en) 1997-03-10 2004-06-11 Janssen Pharmaceutica Nv Farnesyl transferase inhibiting 1,8-annelated quinolinone derivatives substituted with N- or C-linked imidazoles
GB2323783A (en) 1997-04-02 1998-10-07 Ferring Bv Group Holdings Inhibitors of farnesyl protein transferase
BR9809398A (pt) 1997-04-25 2000-06-13 Janssen Pharmaceutica Nv Quinazolinonas que inibem a farnesil transferase
EP1060619B1 (en) 1998-03-05 2002-07-03 Formula One Administration Limited Data communication system
US6303654B1 (en) 1998-03-12 2001-10-16 Wisconsin Alumni Research Foundation Acyclic monoterpenoid derivatives
WO2000001691A1 (en) 1998-07-01 2000-01-13 Merck & Co., Inc. Process for making farnesyl-protein transferase inhibitors
HRP20000904A2 (en) 1998-07-06 2001-12-31 Janssen Pharmaceutica Nv Farnesyl protein transferase inhibitors for treating arthropathies
ATE289602T1 (de) 1998-08-27 2005-03-15 Pfizer Prod Inc Quinolin-2-on-derivate verwendbar als antikrebsmittel
TR200101343T2 (tr) 1998-08-27 2001-09-21 Pfizer Products Inc. Kansere karşı kullanılan maddeler olarak alkinil-ikame edilmiş kinolin-2-on türevleri
BR9916827A (pt) 1998-12-23 2001-10-16 Janssen Pharmaceutica Nv Derivados de quinolina 1,2-anelados
GB0023915D0 (en) 2000-09-29 2000-11-15 Inst Of Ophthalmology Treatment of neuroinflammatory disease
WO2002043733A1 (en) 2000-11-28 2002-06-06 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitors for the treatment of inflammatory bowel disease
EP1390033A1 (en) 2001-04-25 2004-02-25 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitors for treating cachexia
EP1573054A4 (en) * 2002-11-12 2005-12-28 Becton Dickinson Co DIAGNOSIS FOR SEPTICEMIA OR SIRS USING BIOMARKER PROFILES

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