Protein Degrader Reviews, ,

The landscape of cancer treatment is undergoing a fundamental shift, moving beyond traditional methods of protein inhibition toward a more profound and comprehensive therapeutic strategy: targeted protein degradation (TPD). This innovative approach offers a path to tackle previously “undruggable” targets and overcome the resistance mechanisms that often limit the efficacy of conventional small-molecule inhibitors. At its core, TPD is about harnessing the cell’s own quality control machinery—specifically the ubiquitin-proteasome system—to eliminate disease-causing proteins entirely, rather than merely blocking their activity.

The Distinct Advantage of Degradation over Inhibition

Traditional small-molecule inhibitors function on a stoichiometric basis, requiring continuous presence at high concentrations to occupy and block a protein’s active site. They are limited to proteins with well-defined active pockets and often fail to address the non-catalytic or “scaffolding” functions of a target protein.

Targeted degradation strategies—such as those employing bifunctional molecules—represent a true paradigm shift. These molecules act catalytically, continuously recruiting and tagging the unwanted protein for destruction. The key advantages are compelling:

  • Complete Protein Removal: Degradation offers sustained and complete removal of the target protein, providing a more definitive therapeutic effect than transient inhibition.
  • Targeting Non-Catalytic Functions: By eliminating the entire protein, TPD successfully abrogates all its functions, including crucial non-catalytic roles in protein-protein interactions and complex formation, which inhibitors often miss.
  • Overcoming Resistance: Degradation can bypass resistance mechanisms that emerge against inhibitors and can potentially target proteins previously considered inaccessible due to the lack of a suitable binding pocket.
  • Catalytic Mechanism and Dosing: Because the degrader molecule itself is not consumed, it can act at much lower, sub-stoichiometric doses, potentially leading to a wider therapeutic window and reduced off-target side effects.

This profound difference in mechanism positions protein degraders as the next generation of precision medicine.

Targeting Chromatin Modifiers: The NSD Family in Cancer

Among the promising new targets for TPD are chromatin modifiers, enzymes whose aberrant activity is a significant driver of tumor growth and progression. Specifically, the Nuclear Receptor-binding SET Domain (NSD) family of proteins—comprising NSD1, NSD2, and NSD3—are emerging as critical regulators at the nexus of transcriptional dysregulation and anti-tumor immunity.

The NSD proteins are histone methyltransferases that primarily catalyze mono- and di-methylation on histone H3 lysine 36 (H3K36me1/me2), a modification key to regulating gene expression. In cancer, these proteins are frequently overexpressed, mutated, or involved in chromosomal translocations, profoundly contributing to malignant phenotypes.

Interestingly, research reveals that the role of NSD proteins in anti-tumor immunity is complex and context-dependent, sometimes supporting and sometimes suppressing the immune response, based on the cancer type and microenvironment.

Fig.1 NSD1 in anti-tumor immunity.1

NSD Proteins and Immune Evasion: A Dual Role

The diverse functions of the NSD family in immunity are exemplified by the findings on NSD1 and NSD2:

  • NSD1 and “Immune-Cold” Tumors: In certain head and neck squamous cell carcinomas (HNSCCs), loss of NSD1 (e.g., via mutation) paradoxically leads to an “immune-cold” phenotype, characterized by immune cell exclusion, suppressed interferon signaling, and resistance to immune checkpoint blockade. Mechanistically, NSD1 loss reduces the permissive H3K36me2 mark, leading to a compensatory increase in the repressive H3K27me3 mark, silencing key innate immune genes and T-cell-attracting chemokines. This epigenetic antagonism provides a clear rationale for therapeutic intervention, such as targeting the compensatory epigenetic changes to restore immune cell infiltration.
  • NSD2: Context-Dependent Roles: NSD2 demonstrates contrasting roles depending on the cancer type. In prostate cancer and non-small cell lung cancer (NSCLC), high NSD2 expression is often associated with an immunosuppressive environment, promoting resistance to anti-tumor immunity. For instance, in prostate cancer, NSD2 represses antigen presentation genes, leading to reduced Major Histocompatibility Complex Class I (MHC-I) expression and limited T-cell infiltration. Conversely, in colorectal cancer cells, NSD2 loss can dampen anti-tumor immunity by downregulating MHC-I expression in response to immune signals, suggesting a tumor-suppressor-like role in this context. This duality underscores the need for precise, context-specific therapeutic targeting.
  • NSD3 and Immunosuppression: Similar to the suppressive roles seen with NSD1 and NSD2, NSD3 amplification in lung squamous cell carcinoma (LUSC) is consistently linked to a non-inflamed, “immune-cold” tumor microenvironment and poor response to immunotherapy. This phenotype has been linked to elevated Unfolded Protein Response (UPR) signaling, suggesting a new pathway to target in these resistant tumors.
Precision Tools for Epigenetic Targets

The functional complexity and critical role of the NSD family—encompassing both catalytic and non-catalytic functions on histone and non-histone substrates—make them exceptionally compelling targets for TPD technology.

Recent preclinical studies have successfully developed highly selective and potent degraders targeting NSD2 and NSD3. These compounds demonstrate the superior potential of degradation over conventional inhibition:

  • NSD3 Degradation: Molecules designed to degrade NSD3 have shown enhanced anti-cancer activity compared to mere inhibition, suppressing oncogenic pathways and inhibiting tumor growth in models of hematological and lung cancer.
  • NSD2 Degradation: Degraders targeting NSD2 have demonstrated superior potency in suppressing cancer cell growth. Unlike inhibitors that may only affect the localization, these degraders can fully eliminate the protein, leading to a reduction in methylation markers and a comprehensive suppression of all protein functions.

These early results confirm that targeted protein degradation is a viable and potentially superior strategy for comprehensively suppressing the oncogenic activity of NSD proteins. By eliminating the protein entirely, this approach offers the potential to epigenetically reprogram the tumor microenvironment, converting immunologically “cold” tumors into “hot,” immune-responsive ones, particularly for NSD-driven cancers.

The Future of Cancer Treatment

The convergence of epigenetic targets and TPD technology marks an exciting frontier in oncology. Targeted protein degradation provides the selective, potent, and sustained suppression needed to counteract the complex and context-dependent oncogenic roles of the NSD family.

Further mechanistic research is essential to fully map the specific molecular contexts in which these proteins drive immune evasion versus activation. However, the development of these next-generation degraders already lays the groundwork for rational combination therapies—pairing protein degradation with immunotherapies or other epigenetic agents—to maximize efficacy and transform patient outcomes.

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Reference

  1. Chava, Suresh, and Narendra Wajapeyee. “NSD proteins in anti-tumor immunity and their therapeutic targeting by protein degraders.” Cellular and Molecular Life Sciences1 (2025): 1-9. CC BY 4.0. https://doi.org/10.1007/s00018-025-05806-6