Targeted protein degradation in cancer: strategies for undruggable targets and progress towards clinical translation

Targeted protein degradation (TPD) has significantly influenced cancer therapy by enabling the targeting of traditionally undruggable oncogenic drivers such as transcription factors, chromatin remodelers, and mediators of protein-protein interactions, overcoming limitations of conventional inhibitors. This approach harnesses endogenous cellular machinery, specifically the ubiquitin-proteasome system and lysosomal pathways, to achieve precise and efficient elimination of pathogenic proteins. Currently, one degradation-based agent, vepdegestrant, has been approved by FDA, while most agents remain in Phase I or II evaluation, representing significant progress in addressing previously intractable targets in cancers. Nevertheless, a substantial number of disease-relevant proteins remain challenging to modulate effectively. This review focuses on undruggable targets in cancer and distinguishes three target categories: 1) Structurally undruggable targets; 2) Formerly undruggable, now inhibitor-accessible but degradation offers a mechanistic advantage; 3) Non-enzymatic targets. We highlight recent advances in the development of TPD strategies against these elusive targets to a cutoff of 30 September 2026, with the aim of providing a more systematic theoretical foundation for the broader application of the developing TPD in cancer therapeutics.