Discovery of BCL-2-selective degraders for applications in hematological malignancies

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BCL-2 is an antiapoptotic protein that is frequently dysregulated in hematological malignancies. Venetoclax, an FDA-approved selective BCL-2 inhibitor, has demonstrated extraordinary efficacy against acute myeloid leukemia (AML) and lymphoma, although treatment resistance remains a challenge. Targeted protein degradation (TPD) modalities such as molecular glues (MGs) and proteolysis targeting chimeras (PROTACs), both operating by hijacking E3 ubiquitin ligases, constitute emerging topics of drug research. The efficient and selective inactivation of target proteins can circumvent several inhibitor limitations. However, no selective PROTACs are currently available for BCL-2. In our preliminary work, we designed various venetoclax-derived PROTACs that hijack three distinct E3 ubiquitin ligases, some of which degrade BCL-XL but not BCL-2. We postulate that the inaccessibility of lysine residues in BCL-2 to the E3 ligase inside the ternary complex accounts for the hindrance of BCL-2 to our exemplary PROTACs. To prove this hypothesis, we will systematically screen lysine residues and protein areas in BCL-2 and BCL-XL that are essential to trigger ubiquitination. We aim to rationally develop BCL-2-selective degraders by recruiting versatile E3 ligases and altering the linker and BCL-2-binding moieties. Such compounds may overcome toxicity constraints associated with BCL-XL inhibitors and degraders. BCL-2 PROTACs will be extensively screened using a high-throughput, fluorescence-based protein stability assay, and the resulting data will be used for further chemical optimization. Biochemical research, including quantitative proteomics, will be utilized to evaluate the selectivity of promising candidates. In AML cell lines and primary cells, the anticancer activity and interference with the mitochondrial apoptotic pathway will be evaluated. BCL-2-selective PROTACs will be powerful tools for gaining a deeper understanding of BCL-2 functions and may lead to the development of novel cancer treatments. More broadly, our studies may reveal new chemical approaches to overcome resistance to protein degradation.