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  4. Targeted Protein Degradation (TPD): From PROTACs to Molecular Glues

Targeted Protein Degradation (TPD): From PROTACs to Molecular Glues

Proteostasis Multiprotein Complexes and Disease Interprotein Interaction and Disease

Targeted protein degradation is a drug discovery strategy that uses cellular protein degradation systems to selectively eliminate disease-associated proteins, and its core modalities include PROTACs and molecular glue degraders. PROTACs are heterobifunctional molecules that bind a protein of interest and an E3 ubiquitin ligase, while molecular glues enhance protein-protein interactions to promote neo-substrate recruitment and ubiquitination. The field progressed from proteasome inhibitors that validated the ubiquitin-proteasome system as a therapeutic target to programmable degradation platforms using CRBN, VHL, and additional E3 ligases. TPD matters in life sciences because it can remove the whole protein rather than only inhibit catalytic activity, making transcription factors, scaffold proteins, oncogenic fusion proteins, and other historically difficult targets accessible to experimental pharmacology[1][2][3][4].
Mechanistically, ubiquitination proceeds through E1, E2, and E3 enzymes, and E3 ligases confer substrate specificity. K48-linked polyubiquitin chains can direct proteins to the 26S proteasome. PROTACs induce a target protein-PROTAC-E3 ternary complex that drives polyubiquitination and proteasomal degradation. Molecular glues stabilize interactions between E3 ligases and neo-substrates. CRBN and VHL dominate current degrader design, while DCAF15, MDM2, SIAH1, TRIM21, IAP, and other ligases expand the E3 ligase toolbox. BI-3802 induces BCL6 polymerization and SIAH1-mediated BCL6 degradation, supporting molecular glue strategies for transcription factor degradation[2][4][5][6].
Disease applications focus on oncology drug discovery, hematologic malignancies, breast cancer, prostate cancer, brain tumors, and immune-inflammatory targets. PROTACs have entered clinical development, with early progress in estrogen receptor and androgen receptor degradation. BCL6, AR, ER, CDK4/6, BTK, BRD4, IDO1, and RNA-binding proteins represent common experimental targets. Key gaps include cell permeability, bioavailability, pharmacokinetics, target selectivity, ternary-complex design, E3 tissue expression, degradation resistance, and proteome-wide off-target liability. Future studies should optimize linker architecture, E3 ligase recruitment, degrader selectivity, proteomic profiling, and PK/PD relationships to advance PROTACs, molecular glues, LYTACs, and next-generation degradation platforms toward precision therapy[1][3][4][6][7][8].

  • Products
  • Targets/Pathways
Bioactive Molecules
Cat.No. Product Name Disease Area Target Category
HY-101460 Tz-Thalidomide Cancer E3 Ligase Ligand-Linker Conjugates; Drug Derivative Inhibitors & Agonists
HY-103352 L-006235 Metabolic or Endocrine Disease Cathepsin Inhibitors & Agonists
HY-103352R L-006235 (Standard) Metabolic or Endocrine Disease Reference Standards; Cathepsin Reference Standards
HY-105363 RGH-1962 Blood or Cardio-cerebrovascular Disease Others Inhibitors & Agonists
HY-105364 RGH-1875 hydriodide Blood or Cardio-cerebrovascular Disease Others Inhibitors & Agonists
HY-108705 BI-3802 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma; Ovarian Cancer; Urogenital Cancer Molecular Glues; Bcl-2 Family Inhibitors & Agonists
HY-108705R BI-3802 (Standard) / Reference Standards; Molecular Glues; Bcl-2 Family Reference Standards
HY-110078 Eeyarestatin I Viral Infection; Digestive System Inflammation; Cancer; Digestive System Disease p97; Apoptosis Inhibitors & Agonists
HY-112816 MA242 / MDM-2/p53; Apoptosis Inhibitors & Agonists
HY-112816A MA242 free base / MDM-2/p53; Apoptosis Inhibitors & Agonists
HY-114402 ARD-69 Cancer PROTACs; Androgen Receptor Inhibitors & Agonists
HY-114407 TD-428 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Epigenetic Reader Domain Inhibitors & Agonists
HY-122243 IU1-47 Neurodegenerative Disease Deubiquitinase Inhibitors & Agonists
HY-122311 Orniplabin Neurological, Eye or Ear Disease; Inflammation or Immune System Disease Reactive Oxygen Species (ROS) Inhibitors & Agonists
HY-122311A Bis(2R,3R)-Orniplabin / Drug Isomer Inhibitors & Agonists
HY-122653 CCT367766 / PROTACs Inhibitors & Agonists
HY-122653A CCT367766 formic Ovarian Cancer; Urogenital Cancer PROTACs Inhibitors & Agonists
HY-122825 SNIPER(ER)-110 Cancer SNIPERs; Estrogen Receptor/ERR Inhibitors & Agonists
HY-124739 HBX 28258 Cancer Deubiquitinase Inhibitors & Agonists
HY-125593 Dasminapant Cancer IAP; Apoptosis Inhibitors & Agonists
HY-12933 BIIB-028 / HSP Inhibitors & Agonists
HY-130992 Androgen receptor antagonist 1 Prostate Cancer; Urogenital Cancer Androgen Receptor; Ligands for Target Protein for PROTAC Inhibitors & Agonists
HY-133044 Boc-Pip-alkyne-Ph-COOH / PROTAC Linkers Inhibitors & Agonists
HY-133045 VHL Ligand 8 Prostate Cancer; Urogenital Cancer Ligands for E3 Ligase Inhibitors & Agonists
HY-136528 RA-9 Ovarian Cancer; Digestive System Inflammation; Urogenital Cancer; Digestive System Disease Deubiquitinase; Apoptosis Inhibitors & Agonists
HY-137340 WH-10417-099 Cancer PROTACs; Casein Kinase Inhibitors & Agonists
HY-137341 SK-3-91 Cancer PROTACs; YTHDF Inhibitors & Agonists
HY-138642 Vepdegestrant Breast Cancer PROTACs; Estrogen Receptor/ERR Inhibitors & Agonists
HY-138642A (Rac)-Vepdegestrant / Estrogen Receptor/ERR; PROTACs Inhibitors & Agonists
HY-138642S Vepdegestrant-d5 Breast Cancer Isotope-Labeled Compounds Isotope-Labeled Compounds
HY-139340 Photo-lenalidomide-acid / PROTACs Inhibitors & Agonists
HY-139996 Pomalidomide-C5-Dovitinib Cancer FLT3; VEGFR; c-Kit; PROTACs; FGFR; c-Fms; Apoptosis; PDGFR Inhibitors & Agonists
HY-145159 SHP2 protein degrader-1 Cancer SHP2; PROTACs; Phosphatase; Apoptosis Inhibitors & Agonists
HY-145368B Tri-GalNAc(OAc)3-Perfluorophenyl Metabolic or Endocrine Disease LYTACs Inhibitors & Agonists
HY-145925C (S,R)-CFT8634 Cancer PROTACs; Epigenetic Reader Domain Inhibitors & Agonists
HY-148173 NUCC-0223619 / Indoleamine 2,3-Dioxygenase (IDO) Inhibitors & Agonists
HY-149862 ARD-2051 Cancer PROTACs; Androgen Receptor Inhibitors & Agonists
HY-151791 (S,R,S)-AHPC-C6-PEG3-butyl-N3 / ADC Linker Inhibitors & Agonists
HY-153321 Bexobrutideg Inflammation or Immune System Disease PROTACs; Btk Inhibitors & Agonists
HY-153321A (R,R)-Bexobrutideg Cancer; Inflammation or Immune System Disease Drug Isomer; PROTACs; Btk Inhibitors & Agonists
HY-153572A Homo-BacPROTAC7 TFA Mycobacterium Tuberculosis Infection PROTACs; Bacterial Inhibitors & Agonists
HY-153598 LD4172 Immunotherapy for Melanoma; Colorectal Cancer; Cancer Immunology; Digestive System Cancer PROTACs; RIP kinase; Apoptosis Inhibitors & Agonists
HY-153714 Zefamenib Alzheimer's Disease; Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma Epigenetic Reader Domain; Potassium Channel Inhibitors & Agonists
HY-153793 Alcudacigib Metastatic Melanoma DGK; IFNAR; Interleukin Related; ERK Inhibitors & Agonists
HY-153793A Alcudacigib TFA Cancer IFNAR; Interleukin Related; DGK; ERK Inhibitors & Agonists
HY-155063 TRAP1-IN-1 Cancer HSP; Mitochondrial Metabolism Inhibitors & Agonists
HY-156730A KT-333 ammonium / Molecular Glues; STAT Inhibitors & Agonists
HY-156730B KT-333 diammonium / Molecular Glues; STAT Inhibitors & Agonists
HY-156814 HPP-9 Cancer Hedgehog Inhibitors & Agonists
HY-157765 PROTAC ERα Degrader-6 Cancer PROTACs; Estrogen Receptor/ERR Inhibitors & Agonists
HY-159668 DL002 / ADC Linker Inhibitors & Agonists
HY-160438 PBX-7011 Cancer Survivin Inhibitors & Agonists
HY-160438A PBX-7011 mesylate Cancer Survivin Inhibitors & Agonists
HY-160531 IKZF1-degrader-1 Cancer Molecular Glues; IKZF Family Inhibitors & Agonists
HY-161162 aTAG 2139 / DNA/RNA Synthesis Inhibitors & Agonists
HY-16121 CAA-0225 / Cathepsin Inhibitors & Agonists
HY-161324 Tubulin degrader 1 / Microtubule/Tubulin Inhibitors & Agonists
HY-161804 GNF-2-deg Infection PROTACs; Dengue Virus Inhibitors & Agonists
HY-162331 STING Degrader-1 Cancer; Inflammation or Immune System Disease Molecular Glues; STING Inhibitors & Agonists
HY-163502 PROTAC STAT3 degrader-3 Cancer PROTACs; STAT Inhibitors & Agonists
HY-163743 SIC-19 Ovarian Cancer; Urogenital Cancer Salt-inducible Kinase (SIK) Inhibitors & Agonists
HY-163757 PROTAC PD-L1 degrader-1 Cancer; Inflammation or Immune System Disease PROTACs; PD-1/PD-L1 Inhibitors & Agonists
HY-168016 PROTAC YAP degrader-1 Hepatitis B Virus Related Hepatocellular Carcinoma; Skin Cancer PROTACs; YAP Inhibitors & Agonists
HY-168055 (S)-Deoxy-thalidomide Cancer Ligands for E3 Ligase Inhibitors & Agonists
HY-168056 KRAS ligand 5 Others Ligands for Target Protein for PROTAC; Ras Inhibitors & Agonists
HY-168492 TrxR/EGFR-IN-1 / Ferroptosis; EGFR; TrxR; Apoptosis Inhibitors & Agonists
HY-168614 MGD-4 Cancer IKZF Family Inhibitors & Agonists
HY-168615 MGD-28 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma IKZF Family; Casein Kinase Inhibitors & Agonists
HY-168634 SJ46421 Cancer PROTACs; Epigenetic Reader Domain Inhibitors & Agonists
HY-169325 (S)-ACE-OH Cancer Molecular Glues Inhibitors & Agonists
HY-169921 c-Myc inhibitor 15 / c-Myc; Apoptosis Inhibitors & Agonists
HY-170769 FLT3 Ligand-Linker Conjugate 1 Cancer Target Protein Ligand-Linker Conjugates; FLT3 Inhibitors & Agonists
HY-170859 AH078 Cancer PROTACs; Casein Kinase Inhibitors & Agonists
HY-171755 Hsp90-IN-40 / HSP Inhibitors & Agonists
HY-171792 BMS-986497 Acute Myeloid Leukemia Transmembrane Glycoprotein Inhibitors & Agonists
HY-171825 SIAIS001 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Anaplastic lymphoma kinase (ALK) Inhibitors & Agonists
HY-172822 TLT8 Cancer ByeTAC; Btk Inhibitors & Agonists
HY-17439 Salinomycin sodium salt Hypertension; Lung Fibrosis; Rheumatoid Arthritis; Breast Cancer; Colorectal Cancer; Prostate Cancer; Gastric Cancer; Liver Cancer; Ovarian Cancer; Bacterial Infection; Parasitic Infection; Autoimmune Disease; Digestive System Inflammation; Digestive System Cancer; Urogenital Cancer; Neurological, Eye or Ear Disease Wnt; β-catenin; Bacterial; Autophagy; Apoptosis; Antibiotic; Parasite Inhibitors & Agonists
HY-17439R Salinomycin sodium salt (Standard) Cancer Reference Standards; Wnt; β-catenin; Bacterial; Autophagy; Apoptosis; Antibiotic; Parasite Reference Standards
HY-174867 AY-4 Breast Cancer PROTACs; Ferroptosis Inhibitors & Agonists
HY-175179 LO-3-61 Cancer Epigenetic Reader Domain; E1/E2/E3 Enzyme Inhibitors & Agonists
HY-175204 SHP2 protein degrader-3 / AUTACs; SHP2; Apoptosis; Autophagy; Atg8/LC3 Inhibitors & Agonists
HY-175209 Nrf2-IN-4 / Keap1-Nrf2; Ferroptosis; Reactive Oxygen Species (ROS); Atg8/LC3 Inhibitors & Agonists
HY-175209A Nrf2-IN-4 hydrobromide Breast Cancer Keap1-Nrf2; Ferroptosis; Reactive Oxygen Species (ROS); Atg8/LC3 Inhibitors & Agonists
HY-175381 DeFer-2 Cancer PROTACs; Pyroptosis; Reactive Oxygen Species (ROS); Caspase Inhibitors & Agonists
HY-176732 MJ-26 Cancer Epigenetic Reader Domain Inhibitors & Agonists
HY-177893 OZD-MET 01 / PROTACs; c-Met/HGFR Inhibitors & Agonists
HY-178694 DC-PRC2in-01 / Histone Methyltransferase Inhibitors & Agonists
HY-179065 VU0494372 Blood or Cardio-cerebrovascular Disease Potassium Channel Inhibitors & Agonists
HY-180261 GP262 Triple-Negative Breast Cancer; Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; mTOR; PI3K; Apoptosis Inhibitors & Agonists
HY-180548 MRC37 Viral Infection; Inflammation or Immune System Disease E1/E2/E3 Enzyme Inhibitors & Agonists
HY-180961 His-TERRα Breast Cancer PROTACs; Estrogen Receptor/ERR Inhibitors & Agonists
HY-180962 Phe-PEG1-Dasa Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Bcr-Abl Inhibitors & Agonists
HY-180985 Azo-PROTAC-4C-cis Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Bcr-Abl Inhibitors & Agonists
HY-181098 FKA-9i Gastric Cancer; Digestive System Cancer Reactive Oxygen Species (ROS); Apoptosis; p38 MAPK; CDK; Caspase; Bcl-2 Family Inhibitors & Agonists
HY-181296 PROTAC EZH2 Degrader-16 Cancer PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181300 PROTAC EZH2 Degrader-17 Diffuse Large B-cell Lymphoma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181301 PROTAC EZH2 Degrader-18 / PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181305 PROTAC EZH2 Degrader-10 Cancer PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181306 PROTAC EZH2 Degrader-11 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181320 PROTAC EZH2 Degrader-19 Cancer PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181323 PROTAC EZH2 Degrader-22 Cancer PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181324 PROTAC EZH2 Degrader-23 Cancer PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181332 PROTAC EZH2 Degrader-37 Diffuse Large B-cell Lymphoma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181354 PROTAC EZH2 Degrader-36 Diffuse Large B-cell Lymphoma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181357 PROTAC EZH2 Degrader-29 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181359 PROTAC EZH2 Degrader-30 Diffuse Large B-cell Lymphoma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181392 PROTAC EZH2 Degrader-35 Breast Cancer PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181409 PROTAC EZH2 Degrader-40 Diffuse Large B-cell Lymphoma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181412 PROTAC EZH2 Degrader-43 Diffuse Large B-cell Lymphoma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181414 PROTAC EZH2 Degrader-45 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma PROTACs; Histone Methyltransferase Inhibitors & Agonists
HY-181532 IAP ligand 8 Skin Cancer Ligands for E3 Ligase; IAP Inhibitors & Agonists
HY-181533 IAP ligand 9 Skin Cancer Ligands for E3 Ligase; IAP Inhibitors & Agonists
HY-181607 TEAD ligand-Linker Conjugate 3 Others YAP Inhibitors & Agonists
HY-181623 PROTAC BTK degrader-14 Cancer PROTACs; Btk Inhibitors & Agonists
HY-181654 Snail IN-1 Atherosclerosis and Inflammation Epigenetic Reader Domain; CXCR; MMP Inhibitors & Agonists
HY-181695 PROTAC KAT2A/B degrader-1 Small Cell Lung Cancer; Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma; Respiratory Cancer PROTACs; Histone Acetyltransferase Inhibitors & Agonists
HY-181868 Lenalidomide-CO-C7-NH2 Acute Myeloid Leukemia E3 Ligase Ligand-Linker Conjugates Inhibitors & Agonists
HY-181895 PROTAC HyTTD Degrader-1 Cancer RET Inhibitors & Agonists
HY-182370 TKP-5 Skin Inflammation PROTACs; Epigenetic Reader Domain Inhibitors & Agonists
HY-182793 MLL1-IN-1 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma Histone Methyltransferase Inhibitors & Agonists
HY-183768 PROTAC FAK degrader 5 Colorectal Cancer; Digestive System Cancer PROTACs; FAK Inhibitors & Agonists
HY-183878 Zincov Vibrio Cholerae Infection; Glucose Metabolism Bacterial Inhibitors & Agonists
HY-185102 ZBP1 PROTAC-1 Cancer PROTACs Inhibitors & Agonists
HY-19332 Kifunensine Inflammation or Immune System Disease Glycosidase Inhibitors & Agonists
HY-19332R Kifunensine (Standard) Inflammation or Immune System Disease Reference Standards; Glycosidase; Others Reference Standards
HY-19726 NSC59984 Leukemia/Lymphoma/Myeloma; Colorectal Cancer; Leukemia/Lymphoma/Myeloma; Pancreatic Cancer; Ovarian Cancer; Digestive System Cancer; Urogenital Cancer MDM-2/p53 Inhibitors & Agonists
HY-44148 FAK ligand-Linker Conjugate 1 Cancer Target Protein Ligand-Linker Conjugates Inhibitors & Agonists
HY-D3153 PbQ / Apoptosis; Caspase; Microtubule/Tubulin Fluorescent Dyes
HY-E70193 Keratinase / Biochemical Assay Reagents Inhibitors & Agonists
HY-P11703 TRVLNLGPI Others MHC Peptides
HY-P2727 Chondroitinase ABC Neurological, Eye or Ear Disease; Inflammation or Immune System Disease Endogenous Metabolite Inhibitors & Agonists
HY-P3153 Cathepsin K Osteoporosis Cathepsin Inhibitors & Agonists
HY-P990627 Anti-EphA2 Antibody (1C1) Prostate Cancer; Glioma; Urogenital Cancer ADC Antibody; Ephrin Receptor Inhibitors & Agonists
HY-P991381 JST-TfR09 Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma Transferrin Receptor; Reactive Oxygen Species (ROS); Ferroptosis Inhibitors & Agonists
HY-W087383 Thalidomide 5-fluoride Leukemia/Lymphoma/Myeloma; Leukemia/Lymphoma/Myeloma; Digestive System Inflammation; Digestive System Disease Ligands for E3 Ligase; Autophagy; Apoptosis Inhibitors & Agonists

Reference

[1]. Kim S, et al. Targeted protein degradation: therapeutic potential and challenges of PROTACs and molecular glues. J Biomed Transl Res. 2025;26(2):21.

[2]. Brodermann MH, et al. The emerging role of targeted protein degradation to treat and study cancer. J Pathol. 2024;263.

[3]. Castaldi MP, et al. Advances in protein degradation. SLAS Discov. 2021;26:471-473.

[4]. Ramachandran S, et al. Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues. Curr Opin Struct Biol. 2020;67:110-119.

[5]. Rana S, et al. Small molecule induced polymerization of BCL6 facilitates SIAH1 mediated degradation. Signal Transduct Target Ther. 2021;6.

[6]. Thomas E, et al. Targeted degradation of androgen receptor by VNPP433-3β in castration-resistant prostate cancer cells implicates interaction with E3 ligase MDM2 resulting in ubiquitin-proteasomal degradation. Cancers. 2023;15.

[7]. Scholz N, et al. Targeting the ubiquitin system in glioblastoma. Front Oncol. 2020;10.

[8]. Zheng Q, et al. Lysosome-targeting chimera (LYTAC): A silver bullet for targeted degradation of oncogenic membrane proteins. MedComm Oncol. 2024

Keywords：targeted protein degradation | PROTACs | molecular glues | ubiquitin-proteasome system | E3 ligase