HDAC3

Histone Deacetylase 3

Score: 0.559 Price: $0.56 Low Druggability Status: active Wiki: HDAC3

🧠 Neurodegeneration

HYPOTHESES

5

PAPERS

36

KG EDGES

174

DEBATES

1

3D Protein Structure

🧬 HDAC3 — PDB 4A69 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.41

Clinical Stage

Approved

Target Class

Epigenetic Regulator

Safety

0.40

Druggability Analysis

Drug Development0.60

Structural Tractability0.70

Target Class0.70

Safety Profile0.40

Key Metrics

PDB Structures:

5

Known Drugs:

2

Approved:

0

In Clinical Trials:

0

Drug Pipeline (2 compounds)

Druggability Rationale: HDAC3 is highly druggable (score: 0.90) due to its well-characterized zinc-dependent catalytic pocket, validated by two FDA-approved HDAC inhibitors (Vorinostat, Romidepsin) that demonstrate clinical efficacy in cancer. The target belongs to a proven drug class with extensive medicinal chemistry precedent and known inhibitor chemotypes, combined with available AlphaFold structural predictions enabling rational drug design.

Mechanism: Small molecule inhibitor of histone deacetylase enzymatic activity

Drug Pipeline (2 compounds)

Known Drugs:

Vorinostat (Approved) — Cancer

Romidepsin (Approved) — Cancer

Structural Data:

PDB (5) ✓AlphaFold ✓Cryo-EM —

4A69 4QX2 4QXO 6UDB 5WXM

UniProt: O15379

🧬 3D Protein Structure

🧬 HDAC3 — PDB 4A69 Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

Selectivity among class I HDACs (HDAC1, 2, 3, 8) remains challenging given their conserved catalytic domains; however, HDAC3's unique association with the NCoR1 corepressor complex provides opportunities for selective modulation through allosteric or protein-protein interaction inhibitors. Off-target HDAC inhibition may cause undesired hyperacetylation effects, necessitating careful isoform selectivity profiling.

3D Protein Structure

PDB: Open in RCSB AlphaFold model

Interactive 3D viewer powered by RCSB PDB / Mol*. Use mouse to rotate, scroll to zoom.

Clinical Trials (8)

Relevant trials from ClinicalTrials.gov

Active

3

Completed

5

Total Enrollment

536

By Phase

PHASE1: 6 · PHASE2: 2

Randomized Phase IIB Trial of Oral Azacytidine Plus Romidepsin Versus Investigator's Choice in PTCL Recruiting

PHASE2 NCT04747236 n=50

PTCL

Interventions: Azacytidine, Romidepsin, Belinostat

Sponsor: University of Virginia | Started: 2021-02-19

Pembrolizumab and Vorinostat in Patients With Relapsed or Refractory DLBCL, FCL or HL. Active Not Recruiting

PHASE1 NCT03150329 n=52

Grade 3b Follicular Lymphoma, Recurrent B-Cell Lymphoma, Unclassifiabl, Recurrent Classic Hodgkin Lymphoma

Interventions: Laboratory Biomarker Analysis, Pembrolizumab, Vorinostat

Sponsor: City of Hope Medical Center | Started: 2017-07-18

Pembro and Vorinostat for Patients With Stage IV Non-small Cell Lung Cancer (NSCLC) Active Not Recruiting

PHASE1 NCT02638090 n=120

Lung Cancer, Non-small Cell Lung Cancer

Interventions: Vorinostat, Pembrolizumab

Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Started: 2016-03-22

FR901228 in Treating Patients With Metastatic Breast Cancer Completed

PHASE2 NCT00098397 n=37

Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Interventions: romidepsin, laboratory biomarker analysis

Sponsor: National Cancer Institute (NCI) | Started: 2005-02

Vorinostat and Alvocidib in Treating Patients With Advanced Solid Tumors Completed

PHASE1 NCT00324480 n=60

Unspecified Adult Solid Tumor, Protocol

Interventions: alvocidib, vorinostat, pharmacological study

Sponsor: National Cancer Institute (NCI) | Started: 2006-03

Trial for Locally Advanced Breast Cancer Using Vorinostat Plus Chemotherapy Completed

PHASE1 NCT00574587 n=55

Breast Cancer

Interventions: Vorinostat, Paclitaxel, Trastuzumab

Sponsor: Albert Einstein College of Medicine | Started: 2007-12

Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme Completed

PHASE1 NCT00731731 n=125

Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Interventions: 3-Dimensional Conformal Radiation Therap, Cognitive Assessment, Laboratory Biomarker Analysis

Sponsor: National Cancer Institute (NCI) | Started: 2009-07-10

Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction Completed

PHASE1 NCT01638533 n=37

Glioma, Hematopoietic and Lymphoid Cell Neoplasm, Lymphoma

Interventions: Pharmacological Study, Romidepsin

Sponsor: National Cancer Institute (NCI) | Started: 2012-08-03

Linked Hypotheses (3)

Selective HDAC3 Inhibition with Cognitive Enhancement0.779

HDAC3-Selective Inhibition for Clock Reset0.710

HDAC3-Dependent A1 Astrocyte Commitment Window0.611

Linked Experiments (1)

Proposed experiment from debate on Epigenetic clocks and biological aging in neurodegeneration0.400

Scoring Dimensions

Knowledge Graph (20)

activates (2)

HDAC2→HDAC3HDAC3→TRKB

co discussed (5)

HDAC3→TET2HDAC3→KDM6AHDAC3→SIRT6HDAC3→DNMT1HDAC3→FOXO3

expressed in (5)

HDAC11→HDAC3HDAC2→HDAC3HDAC1→HDAC3HDAC3→HDAC6HDAC3→HDAC7

regulates (8)

SIRT6→HDAC3SIRT7→HDAC3SIRT5→HDAC3BDNF→HDAC3SIRT1→HDAC3

▸ Show 3 more

SIRT2→HDAC3SIRT3→HDAC3HDAC3→SIRT4

Debate History (1)

Should HDAC3 (Histone Deacetylase 3) be prioritized as a therapeutic target for 2026-04-21