Senolytic effects of first and second generation BCL-xL/BCL-2 dual degraders

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. 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. 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. 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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