Abstract The evolution of cancer treatment has provided increasingly targeted strategies both in the upfront and relapsed disease settings. Small‐molecule inhibitors and immunotherapy have risen to prominence with chimeric antigen receptor T‐cells, checkpoint inhibitors, kinase inhibitors, and monoclonal antibody therapies being deployed across a range of solid organ and haematological malignancies. However, novel approaches are required to target transcription factors and oncogenic fusion proteins that are central to cancer biology and have generally eluded successful drug development. Thalidomide analogues causing protein degradation have been a cornerstone of treatment in multiple myeloma, but a lack of in‐depth mechanistic understanding initially limited progress in the field. When the protein cereblon (CRBN) was found to mediate thalidomide analogues' action and CRBN's neo‐targets were identified, existing and novel drug development accelerated, with applications outside multiple myeloma, including non‐Hodgkin's lymphoma, myelodysplastic syndrome, and acute leukaemias. Critically, transcription factors were the first canonical targets described. In addition to broadening the application of protein‐degrading drugs, resistance mechanisms are being overcome and targeted protein degradation is widening the scope of druggable proteins against which existing approaches have been ineffective. Examples of targeted protein degraders include molecular glues and proteolysis targeting chimeras (PROTACs): heterobifunctional molecules that bind to proteins of interest and cause proximity‐induced ubiquitination and proteasomal degradation via a linked E3 ligase. Twenty years since their inception, PROTACs have begun progressing through clinical trials, with early success in targeting the oestrogen receptor and androgen receptor in breast and prostate cancer respectively. This review explores important developments in targeted protein degradation to both treat and study cancer. It also considers the potential advantages and challenges in the translational aspects of developing new treatments. © 2024 The Author(s). The Journal of Pathology published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. 

The emerging role of targeted protein degradation to treat and study cancer

The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered “undruggable.” Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples. These compounds serve as molecular glues, redirecting the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of thalidomide analogs demonstrates the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, several additional modalities to trigger protein degradation have been developed and are currently under clinical evaluation. These include heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, disruption of protein interactions, and various other strategies. In this Review, we will provide a concise overview of various degradation modalities, their clinical applications, and potential future directions in the field of protein degradation.

Induced protein degradation for therapeutics: past, present, and future


 IL-1R/TLR activation plays a central role in the pathophysiology of multiple autoimmune and inflammatory diseases via the Myddosome that is dependent on both the kinase and scaffolding functions of Interleukin-1 receptor associated kinase 4 (IRAK4). Therefore, hetero-bifunctional molecules that selectively target IRAK4 for degradation and elimination by the ubiquitin proteasome pathway have the greatest potential to block IL-1R/TLR signaling, including NF-kb activation and cytokine production. To interrogate downstream signaling, phosphorylation events were monitored in monocytes and B cells following TLR7/8 or TLR9 activation, respectively. IRAK4 degradation, but not kinase inhibition, inhibited NF-kb p65 activation and phosphorylation of p38 pathway members by TLR agonists in both cell types. PBMCs pretreated with an IRAK4 degrader and then stimulated with the TLR7/8 agonist, R848, exhibited significantly broader inhibition of cytokines (IL-6, TNFa, IL-8 and IL-1b) compared to those pretreated with a selective IRAK4 kinase inhibitor. Compound washout experiments demonstrated a sustained effect of IRAK4 degrader on both target pharmacodynamics and cytokine inhibition that was differentiated from IRAK4 kinase inhibition. Overall, through removal of both scaffolding and kinase functions, IRAK4 degradation demonstrated greater activity compared to kinase inhibition across multiple TLR stimuli and cell types. These data highlight the potential for IRAK4 degraders to block multiple TLR signaling pathways across different immune cell types and thereby impact TLR/IL-1R-driven inflammatory and autoimmune diseases.

Selective IRAK4 degradation, not kinase inhibition, blocks TLR-activated NF-Kb and p38 Signaling leading to broad cytokine inhibition

https://doi.org/10.1016/j.mcpro.2022.100460

MS-based Detection of Pathogen Antigen Through Immunoprecipitation of Its Proteolytic Peptides

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Selective IRAK4 degradation, not kinase inhibition, blocks TLR-activated NF-Kb and p38 Signaling leading to broad cytokine inhibition

MS-based Detection of Pathogen Antigen Through Immunoprecipitation of Its Proteolytic Peptides