RU2017120287A - ОТБОР БОЛЬНЫХ РАКОМ ДЛЯ ВВЕДЕНИЯ ИНГИБИТОРОВ СИГНАЛЬНОГО ПУТИ Wnt НА ОСНОВАНИИ СТАТУСА МУТАЦИИ RNF43 - Google Patents

ОТБОР БОЛЬНЫХ РАКОМ ДЛЯ ВВЕДЕНИЯ ИНГИБИТОРОВ СИГНАЛЬНОГО ПУТИ Wnt НА ОСНОВАНИИ СТАТУСА МУТАЦИИ RNF43 Download PDF

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RU2017120287A
RU2017120287A RU2017120287A RU2017120287A RU2017120287A RU 2017120287 A RU2017120287 A RU 2017120287A RU 2017120287 A RU2017120287 A RU 2017120287A RU 2017120287 A RU2017120287 A RU 2017120287A RU 2017120287 A RU2017120287 A RU 2017120287A
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pyridin
wnt inhibitor
methyl
rnf43
biomarker
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Фэн Цун
Хуайсян ХАО
Хсин-и ХСИЕХ
Сяомо ЦЗЯН
Цзюнь ЛЮ
Николас НГ
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АйАрЭм ЭлЭлСи
Новартис Аг
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Claims (36)

1. Фарамацевтическая композиция для применения в лечении рака у субъекта, содержащая ингибитор Wnt, где у указанного субъекта, согласно прогнозу, может быть достигнут благоприятный результат от терапевтического введения ингибитора Wnt в соответствии со способом прогнозирования чувствительности роста опухолевых клеток к подавлению ингибитором Wnt, который включает:
(а) определение в полученном у субъекта образце опухолевых клеток уровня биомаркера, выбираемого из группы, состоящей из:
(i) числа копий ДНК в области хромосомы RNF43 и/или в области хромосомы ZNRF3 для определения утраты гетерозиготности;
(ii) секвенированной геномной ДНК, кДНК или РНК из раковых тканей, используемой для обнаружения инактивирующей мутации в гене RNF43 и/или гене ZNRF3;
(iii) экспрессии мРНК RNF43 и/или экспрессии мРНК ZNRF3;
(iv) экспрессии белка RNF43 и/или экспрессии белка ZNRF3;
(v) функционального эффекта утраты гена RNF43 и/или утраты гена ZNRF3;
(vi) комбинации биомаркеров (i)-(v);
(b) сравнение уровня биомаркера в образце опухолевых клеток с контрольным уровнем биомаркера, выбираемым из группы, состоящей из:
(i) контрольного уровня биомаркера, коррелированного с чувствительностью к ингибитору Wnt; и
(ii) контрольного уровня биомаркера, коррелированного с устойчивостью к ингибитору Wnt; и
(с) отбор указанного субъекта как того, у которого, согласно прогнозу, должен быть достигнут благоприятный результат от терапевтического введения ингибитора Wnt, если наличие в опухоли субъекта инактивирующей мутации RNF43 или ZNRF3, уменьшенного числа копий RNF43 или ZNRF2, пониженной экспрессии мРНК или белка RNF43 либо пониженной экспрессии мРНК или белка ZNRF3 свидетельствует о том, что опухоль субъекта, по-видимому, чувствительна к ингибитору Wnt.
2. Фармацевтическая композиция по п.1, где контрольный уровень является нормальным или базовым уровнем биомаркера, уровнем биомаркера в образце здоровой клетки или ткани или контрольным уровнем биомаркера, коррелированным с устойчивостью к ингибитору Wnt.
3. Фармацевтическая композиция по п.1 или 2, где рак представляет собой рак поджелудочной железы.
4. Фармацевтическая композиция по п.1, где ингибитор Wnt представляет собой соединение формулы (1):
Figure 00000001
,
или его фармацевтически приемлемой солью, где:
Х1, Х2, Х3 и Х4 выбирают из N и CR7;
один из элементов Х5, Х6, Х7 и Х8 означает N и другие элементы являются СН;
Х9 выбирают из N и СН;
Z выбирают из фенила, пиразинила, пиридинила, пиридазинила и пиперазинила;
при этом каждый фенил, пиразинил, пиридинил, пиридазинил или пиперазинил элемента Z необязательно замещен группой R6;
R1, R2 и R3 означают водород;
m равен 1;
R4 выбирают из водорода, галогена, дифторметила, трифторметила и метила;
R6 выбирают из водорода, галогена и -С(О)R10, где R10 означает метил; и
R7 выбирают из водорода, галогена, циано, метила и трифторметила.
5. Фармацевтическая композиция по п.1, где ингибитор Wnt представляет собой соединение, выбранное из группы, состоящей из:
N-[5-(3-фторфенил)пиридин-2-ил]-2-[5-метил-6-(пиридазин-4-ил)пиридин-3-ил]ацетамид;
2-[5-метил-6-(2-метилпиридин-4-ил)пиридин-3-ил]-N-[5-(пиразин-2-ил)пиридин-2-ил]ацетамид;
N-(2,3'-бипиридин-6'-ил)-2-(2',3-диметил-2,4'-бипиридин-5-ил)ацетамид;
N-(5-(4-ацетилпиперазин-1-ил)пиридин-2-ил)-2-(2'-метил-3-(трифторметил)-2,4'-бипиридин-5-ил)ацетамид;
N-(5-(4-ацетилпиперазин-1-ил)пиридин-2-ил)-2-(2'-фтор-3-метил-2,4'-бипиридин-5-ил)ацетамид; и
2-(2'-фтор-3-метил-2,4'-бипиридин-5-ил)-N-(5-(пиразин-2-ил)пиридин-2-ил)ацетамид;
или его фармацевтически приемлемой солью.
6. Фармацевтическая композиция по п.1, где ингибитор Wnt представляет собой 2-[5-метил-6-(2-метилпиридин-4-ил)пиридин-3-ил]-N-[5-(пиразин-2-ил)пиридин-2-ил]ацетамид.
RU2017120287A 2012-02-28 2013-02-22 ОТБОР БОЛЬНЫХ РАКОМ ДЛЯ ВВЕДЕНИЯ ИНГИБИТОРОВ СИГНАЛЬНОГО ПУТИ Wnt НА ОСНОВАНИИ СТАТУСА МУТАЦИИ RNF43 RU2017120287A (ru)

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AU2013226323B2 (en) 2016-07-14
HK1199744A1 (en) 2015-07-17
IL233920A0 (en) 2014-09-30
ES2968742T3 (es) 2024-05-13
CL2014002269A1 (es) 2014-12-19
AU2013226323A1 (en) 2014-09-11
RU2636000C2 (ru) 2017-11-17
JP2018172408A (ja) 2018-11-08
MX2014010265A (es) 2015-06-23
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BR112014020233A2 (pt) 2017-07-04
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