Targeted protein degradation for cancer therapy

TY - JOUR

T1 - Targeted protein degradation for cancer therapy

AU - Hinterndorfer, Matthias

AU - Spiteri, Valentina A.

AU - Ciulli, Alessio

AU - Winter, Georg E.

N1 - Publisher Copyright: © Springer Nature Limited 2025.

PY - 2025/7

Y1 - 2025/7

N2 - Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin–proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins. Since its conception over 20 years ago, TPD has gained a lot of attention mainly due to improvements in the design of bifunctional proteolysis targeting chimeras (PROTACs) and understanding the mechanisms underlying molecular glue degraders. Today, PROTACs are on the verge of a first clinical approval and recent structural and mechanistic insights combined with technological leaps promise to unlock the rational design of protein degraders, following the lead of lenalidomide and related clinically approved analogues. At the same time, the TPD universe is expanding at a record speed with the discovery of novel modalities beyond molecular glue degraders and PROTACs. Here we review the recent progress in the field, focusing on newly discovered degrader modalities, the current state of clinical degrader candidates for cancer therapy and upcoming design approaches.

AB - Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin–proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins. Since its conception over 20 years ago, TPD has gained a lot of attention mainly due to improvements in the design of bifunctional proteolysis targeting chimeras (PROTACs) and understanding the mechanisms underlying molecular glue degraders. Today, PROTACs are on the verge of a first clinical approval and recent structural and mechanistic insights combined with technological leaps promise to unlock the rational design of protein degraders, following the lead of lenalidomide and related clinically approved analogues. At the same time, the TPD universe is expanding at a record speed with the discovery of novel modalities beyond molecular glue degraders and PROTACs. Here we review the recent progress in the field, focusing on newly discovered degrader modalities, the current state of clinical degrader candidates for cancer therapy and upcoming design approaches.

U2 - 10.1038/s41568-025-00817-8

DO - 10.1038/s41568-025-00817-8

M3 - Review article

C2 - 40281114

AN - SCOPUS:105003467378

SN - 1474-175X

VL - 25

SP - 493

EP - 516

JO - Nature Reviews Cancer

JF - Nature Reviews Cancer

IS - 7

M1 - e1487

ER -