Figure 4.

Development of novel approaches to selectively kill Sncs. (a) Selectively targeting specific SCAP factors can be enhanced by PROTAC. Here, a drug that binds a SCAP is linked directly to an E3 ligase–targeting moiety to direct rapid and efficient Ub-dependent proteasomal degradation of the SCAP, rendering the Snc vulnerable to apoptosis. (b) To target a cytotoxic drug specifically to Sncs, one approach involves linking a cytotoxic agent to galactoside, which can be cleaved by lysosomal β-galactosidase, the enzyme selectively increased in Sncs (SA-βgal) to release an active toxin. (c) Optimizing senolytic activity by SAR. To optimize the activity of a senolytic, a series of analogs can be generated for testing in different Snc assays. Additional rounds of SAR can be performed to optimize senolytic activity and to improve the drug-like properties of the senolytic. Figure adapted, with permission, from the original figure by Dr. Lei Zhang and Dr. Carolina Soto Palma. Abbreviations: PROTAC, proteolysis-targeting chimera; SA-βgal, senescence-associated β-galactosidase; SAR, structure-activity relationship; SCAP, senescence-associated antiapoptotic pathway; Snc, senescent cell; Ub, ubiquitin.