ROTAC, 분자 접착제, DUBTAC, LYTAC, AUTAC 및 신흥 분해 모달리티-기술 동향, 경쟁 파이프라인 및 세계 시장 전망(2025-2040년)

Executive Summary / Description

Targeted Protein Degradation (TPD) 2.0 moves beyond occupancy-driven inhibition to event-driven pharmacology-hijacking cellular quality-control machinery (UPS, lysosome, autophagy) to eliminate disease-causing proteins, aggregates, and scaffolds once considered "undruggable." The category now spans heterobifunctionals (PROTACs), mono-valent molecular glues, deubiquitinase-tethering (DUBTACs), lysosome-directed degraders (LYTACs), autophagy-targeting chimeras (AUTACs), ATTEC/MITO-TACs, and RNA/protein hybrid degraders. Next-wave platforms emphasize E3 ligase diversity, tissue-specific ligases, glue discovery at scale, covalent chemistries, subcellular localization control, and targeted delivery (including CNS-penetrant degraders).

Why TPD is breaking out:

• Clinically validated degradation of key oncoproteins (e.g., BTK/BRD4 class) and expansion into neurodegeneration, immunology, virology.
• Undruggable proteome access via glue discovery and non-canonical E3 ligases.
• Better PK/PD tolerability from catalytic, sub-stoichiometric action; potential lower dose and deep target suppression.
• Clear partnering appetite and CDMO capability ramp for complex heterobifunctionals.

Market outlook: From ~$2.2B in 2024 (early oncology revenue + upfronts) to $18-25B by 2035 and $40-55B by 2040, driven by:

• First best-in-class degraders in oncology (BTK-resistant, KRAS-adjacent scaffolds, transcription factors)
• Glue-based CNS assets (tau, a-synuclein, TDP-43 pathways)
• Immunology (pathologic kinases, inflammasome adaptors)
• Combination regimens (IO + degrader; kinase-inhibitor + degrader rescue)
• Platform licensing economics (ligase toolkits, glue engines)

Technology Understanding (Mechanistic & Platform Logic)

Modalities & Machinery

• UPS-centric:
  • PROTACs (heterobifunctionals): target binder-linker-E3 ligase ligand (e.g., CRBN, VHL, IAP, MDM2, DCAF family).
  • Molecular glues: monovalent small molecules that stabilize neomorphic PPIs between a target and E3 (e.g., IMiDs-CRBN, non-IMiD glue classes).
  • DUBTACs: recruit deubiquitinases to stabilize desired proteins (gain-of-function diseases).
• Lysosome/Autophagy-centric:
  • LYTACs: extracellular/secreted targets routed to lysosome via ASGPR/CI-M6PR receptors.
  • AUTACs/ATTECs: tags elicit selective autophagy of cytosolic cargo; mitophagy-targeting chimeras for mitochondria.
• Hybrid / Frontier: RNA-targeting degraders (RIBOTACs), degron-editing, light-activated degraders, PROTAC-antibody conjugates.

Key 2.0 Advances

• Ligase expansion beyond CRBN/VHL (e.g., RNF114, DCAF15/16, FEM1B, KEAP1, KLHL family).
• Glue-first discovery platforms: chemoproteomics, DELs, AI PPI predictors, covalent glue design.
• CNS-penetrant chemistries (macrocycle minimization, polarity tuning, linker truncation).
• Subcellular targeting (nucleus, mitochondria, endosome).
• Covalent reversible warheads improving residence time & ternary complex stability.
• Degrader-IO cross-talk (antigen presentation ↑; synthetic lethality).

Development Challenges (and fixes)

• PK: large polar surface areas -> ve/PSA optimization, macrocycle trimming, intramolecular H-bonding.
• Selectivity: unintended neo-substrates -> chemoproteomic screens, degron mapping.
• Resistance: target/ligase mutations -> ligase switching, dual-E3 degraders.
• Tox: cereblon neosubstrate depletion, on-target toxicity -> ligase choice, degron engineering.

Table of Content

1. Introduction & Methodology

• 1.1 TPD 2.0 Scope and definitions
• 1.3 Clinical/regulatory context vs inhibitors and gene therapy

2. Biology of Protein Quality Control

• 2.1 Ubiquitin-proteasome system (E1/E2/E3; degrons)
• 2.2 Lysosome and autophagy pathways
• 2.3 Neomorphic PPIs & induced proximity principles
• 2.4 Degron code & targetability rules

3. Modality Classes & Engineering

• 3.1 PROTACs: linker physics, ternary complex kinetics, cooperativity
• 3.2 Molecular glues: discovery engines (DEL/HTS/chemo-proteomics/AI)
• 3.3 DUBTACs: deubiquitinase selection & stabilization logic
• 3.4 LYTACs: extracellular target scope, receptor choice (ASGPR, CI-M6PR)
• 3.5 AUTACs/ATTEC/MITO-TAC: selective autophagy circuits
• 3.6 Hybrid modalities (RIBOTACs; antibody-PROTAC conjugates; light-switchable degraders)

4. Ligase Landscape & Tissue Targeting

• 4.1 Canonical ligases (CRBN, VHL) - pros/cons
• 4.2 Non-canonical ligases map (DCAF15/16, RNF114, KEAP1, FEM1B, FBXO family)
• 4.3 Tissue-specific ligases (liver, muscle, CNS)
• 4.4 Ligase switching & dual-ligase designs

5. Target Classes & Indication Maps

• 5.1 Oncology: KRAS pathway scaffolds, BET/BRD, CDK, AR/ER variants, BTK C481S
• 5.2 Neuro: tau, a-syn, TDP-43, huntingtin fragments
• 5.3 Immunology/Inflammation: IRAK4, TYK2, inflammasome adaptors
• 5.4 Virology: capsid proteins, replication factors
• 5.5 Rare disease & aggregate proteopathies

6. Clinical Development Landscape

• 6.1 Global pipeline census (by class, stage, indication)
• 6.2 Pivotal/registrational candidates
• 6.3 Safety learnings & off-target liabilities
• 6.4 Resistance biology & next-gen workarounds

7. Competitive & Deal Landscape

• 7.1 Company archetypes (platform vs asset)
• 7.2 Big-pharma alliances & economics

8. Market Access & Commercial Outlook

• 8.1 Pricing analogs vs inhibitors & cell therapy
• 8.2 Reimbursement
• 8.3 Combination strategies & label expansion

9. Forecasts & Scenarios (2025-2040)

• 9.1 TAM/SAM by domain (oncology, neuro, immunology)
• 9.2 Base/Bull/Bear adoption curves

10. Appendix