PROTACs (targeted protein degradation)

01Overview and value chain#

Markers EC: Directive 2001/83/EC + FDA targeted protein degradation guidance | OECD: Bio-pharma | Regulator: FDA (USA), EMA (European Union), NMPA (China)

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.

02US#

The US owns the PROTAC field commercially — Arvinas, Kymera, C4 Therapeutics and Nurix are all US-based, and Arvinas’s vepdegestrant is on track to be the first approved PROTAC.

Arvinas, Kymera, C4, Nurix, FDA#

• Arvinas: vepdegestrant (ARV-471) is a first-in-class estrogen-receptor PROTAC approaching FDA approval for ER+ breast cancer, co-developed with Pfizer; it is the modality’s lead regulatory asset and would be the first approved targeted-protein-degradation drug.
• Kymera Therapeutics: KT-474 is an IRAK4 degrader (co-developed with Sanofi) whose structural basis for selective and potent IRAK4 degradation was published in Nature Communications, underpinning dermatology and autoimmunity indications.
• C4 Therapeutics: reported initial Phase 1 first-in-human results for cemsidomide (CFT7455), a novel MonoDAC IKZF1/3 degrader, in patients with non-Hodgkin’s lymphoma.
• Nurix Therapeutics: NX-5948 is a CNS-penetrant catalytic BTK degrader that breaks established design rules for CNS drugs, opening B-cell malignancies with CNS involvement.
• FDA framework: PROTAC degraders are reviewed as small-molecule NDA drugs under FDA guidance; vepdegestrant’s approaching approval would establish the first targeted-protein-degradation regulatory precedent.

03CN#

China’s targeted-protein-degradation field is anchored by BeiGene’s BGB-16673 chimeric degrader, with a broader pipeline of CRBN-recruiting degraders from domestic biotechs.

BeiGene, NMPA, domestic pipeline#

• BeiGene: BGB-16673 is a BTK chimeric degrader (CEpD platform) whose CaDAnCe-101 Phase 1 data in relapsed/refractory CLL/SLL was reported at EHA 2026, extending BeiGene’s global haematology franchise into degradation.
• Domestic pipeline: Chinese biotechs (e.g. Cullgen and peers) are building CRBN- and VHL-recruiting degrader pipelines, with several entering clinical development behind the US leaders.
• NMPA framework: degraders are reviewed under the NMPA small-molecule drug framework, with China’s deeper biotech investment pulling the modality forward domestically.

04EU#

Europe’s role in PROTACs is mainly through partnership — Sanofi’s co-development of Kymera’s KT-474 — and the basic-science origin of the modality, with EU regulators preparing for the first degrader MAA.

Sanofi-Kymera partnership, EMA, basic-science origin#

• Sanofi-Kymera partnership: Sanofi (France) co-develops Kymera’s KT-474 IRAK4 degrader, making Europe a commercial partner on one of the modality’s lead immunology assets even though the originator is US-based.
• EMA framework: degraders will be reviewed as small-molecule MAA drugs by the European Medicines Agency under Directive 2001/83/EC; no degrader is yet EU-approved.
• Basic-science origin: the PROTAC concept rests on academic ubiquitin-proteasome biology, and EU pharma (Boehringer Ingelheim, Novartis) maintains early-stage degrader R&D alongside partners.

05Leading companies and research institutes#

06Tech stack and innovations#

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.

07Value chains and production pipelines#

Industrial pipeline of a PROTAC degrader drug (NDA / MAA, Directive 2001/83/EC)#

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Target & E3 selection  │ ───> │ 2. Degrader design        │
└───────────────────────────┘      └───────────────────────────┘
                                                   │
                                                   ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Preclinical & clinical │ <─── │ 3. Synthesis & CMC        │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Regulatory & approval  │ ───> │ 6. Launch & PV            │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Target and E3 selection

A disease protein (ER, IRAK4, IKZF1/3, BTK) is identified as undruggable-by-inhibition or where catalytic removal is advantageous, and a recruiting E3 ligase (CRBN or VHL) is chosen based on target expression and tissue access.

Stage 2: Degrader design

A target-binding warhead and an E3-ligand (e.g. cereblon or VHL ligand) are joined by a tuned linker into a bifunctional molecule, optimised for ternary-complex formation, cooperativity and degradation efficiency.

Stage 3: Synthesis and CMC

Medicinal chemistry scales the bifunctional molecule under small-molecule GMP, optimising oral bioavailability and DMPK — the central challenge that distinguishes a degrader drug candidate from a tool compound.

Stage 4: Preclinical and clinical

IND-enabling degradation PD/PK, safety and efficacy studies support first-in-human trials; cemsidomide (CFT7455), NX-5948 and BGB-16673 are all in Phase 1, and vepdegestrant is approaching approval.

Stage 5: Regulatory and approval

A NDA (US) or MAA (EU) is filed as a small molecule under Directive 2001/83/EC; vepdegestrant’s approaching FDA approval would establish the first targeted-protein-degradation regulatory precedent.

Stage 6: Launch and pharmacovigilance

Following approval, the degrader launches under the small-molecule pharmacovigilance regime, with real-world degradation-PD monitoring that the modality has not yet seen at scale.