The PROTAC DT2216 Targets Cancer by Promoting BCL-X_L Degradation

Overexpression of antiapoptotic proteins in the B-cell lymphoma (BCL) family is a common feature of many cancers. In particular, BCL extra large (BCL-X_L) is a target of interest due to its high expression in solid tumors and some leukemias, but development of drugs targeting BCL-X_L has been thwarted by thrombocytopenia. Building on ABT263, a small-molecule BCL2/BCL-X_L inhibitor that exhibits this dose-limiting toxicity, Khan, Zhang, Lv, and colleagues developed a cell-selective proteolysis-targeting chimera (PROTAC), dubbed DT2216, with not only reduced platelet toxicity, but also improved antitumor efficacy relative to ABT263. This PROTAC was designed with a BCL2/BCL-X_L–binding moiety derived from ABT263 joined via an empirically optimized linker to a ligand of the Von Hippel-Lindau (VHL) E3 ligase, which is not highly expressed in platelets. DT2216 was confirmed to cause BCL-X_L–specific ubiquitination and subsequent proteasome-mediated degradation while sparing other BCL family members despite the ABT263-derived moiety's affinity for BCL2; this may be due to an inability of DT2216 to form a stable ternary complex with BCL2 and VHL in cells. In mouse experiments using T-cell acute lymphoblastic leukemia (T-ALL) xenografts, therapeutically equivalent doses of ABT263 and the PROTAC DT2216 exhibited marked differences in their effects on platelets, with DT2216 producing far lower platelet toxicity. The antitumor efficacy of DT2216 was associated with its ability to induce degradation of BCL-X_L, consistent with the notion that DT2216 acts as a BCL-X_L–specific PROTAC in vivo. Additionally, DT2216 exhibited synergistic effects with BCL-family inhibitors and conventional chemotherapy in cell line–derived xenograft models dependent on multiple BCL-family proteins as well as in a T-ALL patient-derived xenograft model that was highly chemotherapy resistant. In summary, the authors have developed a novel drug targeting the elusive BCL-X_L with improved efficacy and reduced toxicity compared to its predecessor, although further work would be needed to optimize the dose. Further, this work demonstrates how PROTACs that bind tissue-specific E3 ligases can be used to target the drugs to the desired sites, limiting their toxicity in other tissues.

Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-X_L PROTAC degrader achieves safe and potent antitumor activity. Nat Med 2019;25:1938–47.

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