БИОХИМИЯ, 2020, том 85, вып. 10, с. 1421–1441

УДК 577.24

Таргетирование белков семейства Bcl-2: что, где, когда?

Обзор

© 2020 В.В. Сеничкин 1, Н.В. Первушин 1, А.П. Зуев 1, Б. Животовский 1,2, Г.С. Копеина 1*

Московский государственный университет имени М.В. Ломоносова, факультет фундаментальной медицины, 119991 Москва, Россия; электронная почта: lirroster@gmail.com

Институт медицины окружающей среды, Каролинский институт, 17177 Стокгольм, Швеция

Поступила в редакцию 15.07.2020
После доработки 15.07.2020
Принята к публикации 08.08.2020

DOI: 10.31857/S0320972520100097

КЛЮЧЕВЫЕ СЛОВА: апоптоз, Bcl-2 семейство, противоопухолевая терапия, BH3-миметики.

Аннотация

Белки семейства Bcl-2 являются регуляторами апоптоза, одного из наиболее изученных типов программируемой клеточной гибели. Данное семейство белков представлено как про-, так и антиапоптотическими членами. Антиапоптотические белки семейства Bcl-2 нередко используются опухолевыми клетками в качестве механизма устойчивости к гибели, играя важную роль как в процессе возникновения онкологических заболеваний, так и в приобретении злокачественными клетками резистентности к терапевтическим воздействиям. Следовательно, эти белки представляют собой привлекательные мишени для противоопухолевой терапии. Детальное изучение взаимодействий между Bcl-2 белками, лежащих в основе регуляции запуска апоптоза, позволило сделать существенный прорыв в разработке высокоселективных ингибиторов отдельных антиапоптотических представителей семейства. В настоящее время данные вещества активно изучают на доклинических и клинических стадиях, и большим прорывом можно считать одобрение для медицинского применения Венетоклакса, селективного ингибитора белка Bcl-2. Подавление активности антиапоптотических белков Bcl-2 семейства обладает существенным терапевтическим потенциалом, который только предстоит раскрыть. В грядущую эру персонализированной медицины необходимо детальное изучение механизмов, ответственных за чувствительность или резистентность опухолевых клеток к различным терапевтическим агентам, а также подбор наиболее эффективных комбинаций. В обзоре рассмотрены существующие сведения о фундаментальных основах функционирования белков семейства Bcl-2, принципах их ингибирования с помощью малых молекул, успехах такого подхода в противоопухолевой терапии и, наконец, биохимических особенностях, которые могут послужить основой для дальнейшего совершенствования использования ингибиторов антиапоптотических белков семейства Bcl-2 в терапии опухолевых заболеваний.

Сноски

* Адресат для корреспонденции.

Финансирование

Работа выполнена при поддержке гранта РНФ (проект 17-75-20102). Работа в лабораториях авторов также поддержана грантами РФФИ (20-015-00500), Шведским (190345) и Стокгольмским (181301) онкологическими фондами.

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая работа не содержит описания выполненных авторами исследований с участием людей или использованием животных в качестве объектов.

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