pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2026-14-2-136-146pmedpharm-1862Research ArticleОБЗОРЫREVIEWСенолитические эффекты первого и второго поколения двойных деградаторов BCL-xL/BCL-2Senolytic effects of first and second generation BCL-xL/BCL-2 dual degradershttps://orcid.org/0000-0003-2458-922XБережнаяЕ. С.BerezhnayaE. S.

доктор фармацевтических наук, доцент, заведующий кафедрой фармакологии и клинической фармакологии ФГБОУ ВО РостГМУ Минздрава России. 

Россия, 344022, г. Ростов-на-Дону, пер. Нахичеванский, д. 29.

Doctor of Sciences (Pharmacy), Assistant Professor, Head of the Department of Pharmacology and Clinical Pharmacology, Rostov State Medical University.

29 Nakhichevansky Ln., Rostov-on-Don, Russia, 344022.

bereznoy7@yandex.ruhttps://orcid.org/0009-0008-9332-6179СавустьяненкоА. В.SavustyanenkoA. V.

кандидат медицинских наук, доцент кафедры фармакологии и клинической фармакологии ФГБОУ ВО РостГМУ Минздрава России.

Россия, 344022, г. Ростов-на-Дону, пер. Нахичеванский, д. 29.

Candidate of Sciences (Medicine), Assistant Professor of the Department of Pharmacology and Clinical Pharmacology, Rostov State Medical University.

29 Nakhichevansky Ln., Rostov-on-Don, Russia, 344022.

savustyanenko@yandex.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Ростовский государственный медицинский университет» Министерства здравоохранения Российской Федерации.РоссияRostov State Medical University.Russian Federation202629042026142136146Copyright © Бережная Е.С., Савустьяненко А.В., 20262026Бережная Е.С., Савустьяненко А.В.Berezhnaya E.S., Savustyanenko A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/1862Цель

Цель. Провести литературный обзор современных данных о сенолитических эффектах двойных деградаторов BCL-xL/BCL-2, включая доступные молекулы, механизм их действия, эффективность и безопасность.

Материалы и методы

Материалы и методы. Поиск литературы выполнен в базах PubMed, Science Direct, SciELO по ключевым словам: «senolytics», «BCL-xL/BCL-2 dual degraders», «proteolysis targeting chimeras», «753b», «WH244». В базе eLIBRARY.ru использовали следующие ключевые запросы: «сенолитики», «двойные деградаторы BCL-xL/BCL-2», «протеолиз-направленные химеры», «753b», «WH244».

Результаты

Результаты. Накопление в организме небольшого количества стареющих (сенесцентных) клеток благодаря высвобождению ими сенесцентно-ассоциированного секреторного фенотипа (SASP) способствует уничтожению старых и повреждённых клеток. Однако, когда сенесцентных клеток становится много, SASP запускает хронический воспалительный процесс, который ускоряет старение и ведет к развитию возраст-связанных заболеваний, таких как рак, сахарный диабет, атеросклероз и пр. Следовательно, возникает необходимость в разработке сенолитиков — лекарственных препаратов, направленных на уничтожение сенесцентных клеток. Один из возможных путей достижения этого сводится к фармакологической индукции апоптоза. По данным литературы с помощью технологии PROTACs была создана химерная молекула 753b. Один ее конец связывается с E3-лигазой, другой с антиапоптотическими белками (BCL-xL или BCL-2). В результате все эти молекулы сближаются в пространстве, формируя тройной комплекс. Благодаря близости E3-лигаза присоединяет молекулы убиквитина к антиапоптотическим белкам, после чего протеосома их разрушает. Когда BCL-xL и BCL-2 разрушены, происходит апоптоз сенесцентных клеток. Молекулу 753b относят к первому поколению двойных деградаторов BCL-xL/BCL-2. В доклинических исследованиях была продемонстрирована ее антисенесцентная и противоопухолевая эффективность, без развития выраженной тромбоцитопении. На базе молекулы 753b за счёт двух модификаций был разработан ее более сильный аналог — молекула WH244, которую относят ко второму поколению двойных деградаторов BCL-xL/BCL-2.

Заключение

Заключение. Учитывая представленные в литературных источниках данные по эффективности и безопасности, требуется дальнейшее всестороннее исследование молекул 753b, WH244 и/или их производных, в том числе и в клинических исследованиях.

The aim

The aim. To conduct a literature review of current data on the senolytic effects of dual BCL-xL/BCL-2 degraders, including available molecules, their mechanism of action, efficacy, and safety.

Materials and Methods

Materials and Methods. Literature search was performed in PubMed, Science Direct, and SciELO databases using the keywords: “senolytics”, “BCL-xL/BCL-2 dual degraders”, “proteolysis targeting chimeras”, “753b”, “WH244”. In the eLIBRARY.ru database were used the next keywords: «сенолитики», «двойные деградаторы BCL-xL/BCL-2», «протеолиз-направленные химеры», «753b», «WH244».

Results

Results. The accumulation of a small number of senescent cells in the body, due to their release of the senescence-associated secretory phenotype (SASP), contributes to the elimination of old and damaged cells. However, when the number of senescent cells becomes large, SASP triggers a chronic inflammatory process that accelerates aging and leads to the development of age-related diseases such as cancer, diabetes mellitus, atherosclerosis, etc. Therefore, there is a need to develop senolytics — drugs aimed to eliminate senescent cells. One possible way to achieve this is through the pharmacological induction of apoptosis. According to literature data, a chimeric molecule, 753b, was created using PROTACs technology. One end of it binds to an E3 ligase, the other to anti-apoptotic proteins (BCL-xL or BCL-2). As a result, all these molecules are brought together in space, forming a ternary complex. Due to proximity, the E3 ligase attaches ubiquitin molecules to the anti-apoptotic proteins, after which the proteasome destroys them. When BCL-xL and BCL-2 are degraded, apoptosis of senescent cells occurs. The molecule 753b is classified as a first-generation dual BCL-xL/BCL-2 degrader. Its anti-senescence and anti-tumor efficacy has been demonstrated in preclinical studies without the development of significant thrombocytopenia. Based on molecule 753b, a more potent analog was developed through two modifications — molecule WH244, which is classified as a second-generation dual BCL-xL/BCL-2 degrader.

Conclusion

Conclusion. Considering the data on efficacy and safety presented in the literature sources, further comprehensive research on molecules 753b, WH244, and/or their derivatives is required, including in clinical studies.

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The authors declare that there are no conflicts of interest present.