Targeted protein degradation: from mechanisms to clinic

Nat Rev Mol Cell Biol 25, 740–757 (2024)

https://doi.org/10.1038/s41580-024-00729-9

Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.

a, The ubiquitin proteasome pathway. The ubiquitylation pathway is a multi-enzyme cascade that canonically utilizes one of two E1 activating enzymes, a range of E2 enzymes and an E3 ubiquitin ligase to achieve transfer of ubiquitin to the substrate. (1) The E1 adenylates the C-terminal carboxyl group of ubiquitin in an ATP-dependent process known as activation. (2) Ubiquitin is transferred to a cysteine residue on E1. (3) Ubiquitin is transferred to the active-site cysteine of an E2 enzyme. For most ligases, (4) E2-bound ubiquitin binds to an E3 ligase and (5) discharges the ubiquitin to a proximal substrate wherein ubiquitin forms an isopeptide bond, typically with a lysine of the substrate. Some ligases such as HECT or RBR involve an intermediate step of ubiquitin being transferred to an active-site cysteine in the ligase. (6) Ubiquitylation of the substrate can lead to (7) the protein being shuttled to proteasome and degraded or (8) various signalling events. (9) The process of ubiquitylation is countered by the removal of ubiquitin catalysed by deubiquitinase enzymes (DUBs). b, Two main types of degrons. Linear degron exemplified by peptide Nrf2, which is recognized by E3 ligase CRL3KEAP1 for degradation (Protein Data Bank (PDB) code 2DYH). Structural degron, the alpha helix of p53, is recognized by its cognate E3 ligase MDM2 (PDB: 1YCR). c, Conditional protein degrons. Post-translational protein modification can be a trigger for degradation. In normoxia or high oxygen concentrations, HIF-1α is hydroxylated on proline residues by iron-dependent and oxygen-dependent prolyl hydroxylases (PHD1, PHD2 and PHD3) producing a degron recognized by an E3 ligase CRL2VHL, resulting in its ubiquitination and degradation. By contrast, in hypoxia, the hydroxylation process is impaired and HIF-1α forms a complex with HIF-1β; the transcriptional coactivator p300–CPB binds hypoxia response element (HRE) and activates transcription. d, General architecture of cullin-RING ligases (CRLs). CRL complexes are formed of one of the seven cullin proteins (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 or CUL7) bound to an adaptor protein (such as DDB1) and substrate receptor (such as CRBN). The example shows a model of a fully neddylated CRLCRBN E3 ligase bound to dBET6 PROTAC in complex with BRD4BD1, with the E3 ligase engaged with E2 UBE2D2 charged with ubiquitin. The model was composed by combining structures of parts of the complex and alignment over a common subunit of CRBN–dBET6–BRD4BD1 (PDB: 6BOY), DDB1 (PDB: 4A0K) and CRL4–RBX1–NEDD8–UBE2D2–ubiquitin (PDB: 8B3I).

• 논문은 소분자 기반으로 특정 단백질의 선택적 분해를 유도하는 Targeted Protein Degradation(TPD) 기술에 대해 설명함. TPD는 PROTAC(Proteolysis Targeting Chimeras)와 Molecular Glue Degraders라는 두 주요 기법으로 구분할 수 있음. 이 기술은 기존 접근법으로는 공략할 수 없었던 단백질들을 표적화할 수 있다는 점에서 기존 기법과 차별화 됨.