Therapeutics that target chromatin landscape and key regulators: overview of putative and novel therapeutics for IBD based on their potential to target chromatin modifiers or key regulators
| Putative effect in IBD | Compound | Target | IBD-related preclinical studies | Clinical trials (phase) | |
| HDAC inhibitors | Promote acetylation in DREs leading to increased transcription of genes in murine and human immune cells and colonic mucosa associated with reduction of disease severity and inflammation. | Sodium butyrate | Isoform 1–5, 7–9143 | Human,144 mouse107 145 146 | UC (NCT01282905), shigellosis (II) |
| Valproic acid | Isoform 1–3, 8113 | Human,105 111 mouse100 109 | Solid tumours (II), Alzheimer’s disease (I), ALPS (II), schizophrenia (IIII), glycogen storage disease type V (II), SMA (II), supranuclear palsy (II), bipolar disorder (III), HIV (I), leukaemia (II) | ||
| Tacedinaline | Isoform 1–3147 | Human147 | MM(II), solid tumours (III), MDS (II) | ||
| Quisinostat | Isoform 1–11113 | Human148 | Leukaemia (I), MM (I), lymphoma (I), solid tumours (II) | ||
| Trichostatin A | Isoform 1, 3, 4, 6, 10 | Mouse110 149 150 | – | ||
| Vorinostat/suberoylanilide hydroxamic acid | Isoform 1–11113 | Human, mouse100 109 | CTCL (II), advanced clinical stages for anticancer treatment (Ali, 2018) | ||
| Givinostat | Isoform 1–10 | Mouse110 149–151 | Leukaemia (II), MM (II), CTCL (III), systemic juvenile idiopathic arthritis (III), polycythaemia vera (III) | ||
| Entinostat | Isoform 1–3, 9113 | Human,105 111 mouse151 | Leukaemia (I), solid tumours (II) | ||
| Panobinostat | Isoform 1–11116 | Human,152 mouse110 149 150 | HIV(II), AML(I), lymphoma (III), MM (II), leukaemia (I), CTCL (III), solid tumours (II) | ||
| Resminostat | Isoform 1, 3, 6, 8116 | – | Lymphoma (II), solid tumours (II) | ||
| Mocetinostat | Isoform 1–5, 9–11116 | Guinea pig,153 human154 | MDS (II), leukaemia (II), lymphoma (II), solid tumours (II) | ||
| Abexinostat | Isoform 1–3, 6, 10116 | Human155 | Lymphoma (II), solid tumours (II) | ||
| Pracinostat | Isoform 1–4, 7–11113 | Human156 | MDS (II), myeloproliferative disease (II), leukaemia (I), solid tumours (I) | ||
| Belinostat | Isoform 1–4, 6–9113 | Human157 | Lymphoma (II), leukaemia (II), MDS (II), MM (II), solid tumours (II) | ||
| Tubastatin A | Isoform 6158 | Human,159 mouse160 | – | ||
| Tubacin | Isoform 6161 | Mouse160 | – | ||
| Santacruzamate A | Isoform 2, 4, 6147 | Human147 | – | ||
| Romidepsin | Isoform 1, 2147 | Human147 | Lymphoma (II), solid tumours (II) | ||
| Abexinostat | Isoform 2, 3, 6, 10 | Human155 | Lymphoma (II), MM (II), leukaemia (II), solid tumours (II) | ||
| CUDC-101 | Isoform 1–10 | – | Solid tumours (I) | ||
| BET inhibitors | JQ1 | BET | Human,120 162 mouse120 | None | |
| Preferential inhibition of inflammation-associated gene expression involved in proinflammatory activity of murine and mouse monocyte, macrophages and T lymphocytes. | I-BET762 | BET | Mouse120 | Solid tumours (II) | |
| I-BET151 | BET | Mouse120 | – | ||
| ZEN3694 | BET | – | Solid tumours (II) | ||
| INCB054329 | BET | – | Solid tumours and haematological malignancies (II) | ||
| BMS-986158 | BET | – | Solid tumours(II) | ||
| FT-1101 | BET | – | Leukaemia (I), MDS (I) lymphoma (I) | ||
| RO6870810/TEN-010 | BET | – | MM (I), leukaemia (I), MDS (I), solid tumours (I) | ||
| RVX000222 | BET | Human163 | Diabetes mellitus type 2 (III), cardiovascular disease (III), Fabry disease (I), chronic kidney failure (I) | ||
| CPI-0610 | BET | – | MM (I), lymphoma (I), myelofibrosis (II), solid tumours (II) | ||
| OTX015/MK-8628 | BET | – | MDS (I), lymphoma (I), solid tumours (I) | ||
| Methyltransferase inhibitors | Upregulation of FOXP3 to increase EZH2 expression. | Decitabine (5-aza-2′-deoxycytidine or 5-aza-dC) | DNA methyltransferase | Human164 | – |
| Tazemetostat | EZH2 | Mouse122 | Lymphoma (II), solid tumours (II) | ||
| SHR2554 | EZH2 | – | Lymphoma (I) | ||
| CPI-1205 | EZH2 | Human165 | Lymphoma (I), solid tumours (II) | ||
| Key regulator modulators | NFKB inhibition. | Dehydroxymethylepoxyquinomicin | NFKB (nuclear translocation) | Mouse132 | – |
| Curcumin | NFKB | Mouse166 | IBD (III) (NCT00779493)167 | ||
| NFKB decoy oligonucleotide | NFKB | Rat131 | Atopic dermatitis (II) | ||
| HNF4a agonists show protective effect. | C14-C18 fatty acids | HNF4A | Crystal structure128 129 | – | |
| Inhibition of the JAK/STAT pathway. | Tofacitinib | JAK1, JAK2, JAK3, TYK2 | Human168 | Crohn’s disease (II)136 and UC (III),51 immune-related diseases (III) | |
| Peficitinib | JAK1, JAK3 | Human168 | UC (II),116 rheumatoid arthritis (II) | ||
| Upadacitinib | JAK1 | Human168 | Crohn’s disease (II) (NCT02365649) | ||
| Filgotinib | JAK1 | Human168 | Crohn’s disease (II),117 immune-related diseases (II) |
↵ClinicalTrials.gov was consulted for data on clinical trials and phases that are executed for each listed compound. We define IBD-related preclinical data as studies performed on IBD-related cells or tissues.
AML, acute myeloid leukaemia; ALPS, autoimmune lymphoproliferative syndrome; BET, bromodomain and extraterminal; CTCL, cutaneous T cell lymphoma; DRE, DNA regulatory element; EZH2, enhancer of zeste homolog 2; HDAC, histone deacetylase; JAK, Janus kinase; MDS, myelodysplastic syndrome; MM, multiple myeloma; NFKB, nuclear factor kappa B; SMA, spinal muscular atrophy.