PROTACs (targeted protein degradation)

PROTACs (proteolysis-targeting chimeras) and related targeted-protein-degradation (TPD) molecules are bifunctional small molecules: one end binds a disease target protein and the other an E3 ubiquitin ligase, bringing the two together so the ligase tags the target for proteasomal destruction. Because a single PROTAC molecule catalytically destroys many target copies (event-driven pharmacology), it can drug proteins that conventional inhibitors cannot — scaffolds, transcription factors, aggregated proteins. Arvinas’s vepdegestrant (ARV-471) is a first-in-class estrogen-receptor PROTAC approaching FDA approval for breast cancer (co-developed with Pfizer); Kymera’s KT-474 (IRAK4 degrader, with Sanofi) has the structural basis of its potency and selectivity published in Nature Communications; C4 Therapeutics reported first-in-human Phase 1 results for cemsidomide (CFT7455, MonoDAC IKZF1/3 degrader) in non-Hodgkin’s lymphoma; Nurix’s NX-5948 is a CNS-penetrant BTK degrader that breaks established CNS-drug design rules; and BeiGene’s BGB-16673 BTK chimeric degrader reported CaDAnCe-101 Phase 1 data in relapsed/refractory CLL/SLL at EHA 2026.

The key directions of PROTACs are:

1. Estrogen-receptor PROTACs (Oncology Degrader): first-in-class ER degrader for ER+ breast cancer, the modality’s lead asset approaching approval — Arvinas (vepdegestrant/ARV-471, with Pfizer).
2. Immunology degraders (Immunology Degrader): IRAK4 and IKZF1/3 degraders for autoimmune and haematological disease — Kymera (KT-474 IRAK4, with Sanofi), C4 Therapeutics (cemsidomide/CFT7455 IKZF).
3. BTK degraders (BTK Degrader): catalytic BTK destruction for B-cell malignancies, including CNS-penetrant designs — Nurix (NX-5948), BeiGene (BGB-16673).
4. Degrader chemistry platforms (Degradation Platform): cereblon- and VHL-recruiting E3 ligands, MonoDAC/CEpD scaffolds, and the linker/warhead design that enables catalytic, sub-stoichiometric destruction.

Sectoral value chain#

[disease protein + E3 ligase] ──> [bifunctional degrader design + synthesis] ──> [oral small-molecule degrader]
                                              │
                                     (catalytic proteasomal destruction)
                                              │
                                              ▼
[clinical candidate] <─── [degradation PD/PK + Phase 1-3 trials] <─────┘

Value chain levels#

Cross-cutting technologies of the sector:

• E3 ligase recruitment (E3 Ligase Recruitment): cereblon (CRBN) and von Hippel-Lindau (VHL) are the dominant recruited E3 ligases; the choice governs which tissues and targets are addressable.
• Event-driven pharmacology (Catalytic Degradation): because one degrader molecule destroys many target copies, PROTACs can work at lower exposure and against scaffolds and aggregation-prone proteins undruggable by inhibitors.
• Oral small-molecule profile (Oral Degrader): unlike antibody or cell therapy, PROTACs aim for oral bioavailability, the central CMC and medicinal-chemistry challenge.

The stack pairs target- and E3-ligand selection with bifunctional linker engineering and oral small-molecule CMC, delivering catalytic destruction of a disease protein.

1. Estrogen-receptor PROTACs (Oncology Degrader):
   • Arvinas’s vepdegestrant (ARV-471) is a first-in-class ER PROTAC approaching FDA approval for ER+ breast cancer, co-developed with Pfizer — the modality’s lead asset and first regulatory test.
2. Immunology degraders (Immunology Degrader):
   • Kymera’s KT-474 (IRAK4, with Sanofi) has the structural basis for its selective, potent degradation published in Nature Communications; C4’s cemsidomide (CFT7455 MonoDAC IKZF1/3 degrader) reported initial Phase 1 results in non-Hodgkin’s lymphoma.
3. BTK degraders (BTK Degrader):
   • Nurix’s NX-5948 is a CNS-penetrant catalytic BTK degrader that breaks established CNS-drug design rules, and BeiGene’s BGB-16673 (CEpD platform) reported CaDAnCe-101 Phase 1 data in relapsed/refractory CLL/SLL at EHA 2026.
4. Degradation platforms (Degradation Platform):
   • Cereblon- and VHL-recruiting E3 ligands, MonoDAC (C4) and CEpD (BeiGene) scaffolds embody the linker/warhead engineering that makes a single molecule catalytic and orally bioavailable.