Examples of epigenetic targeted therapy in AML in various stages of development
| Class of epigenetic regulator . | Target . | Compound . | Phase of development . |
|---|---|---|---|
| DNA methyltransferase | DNMTs | Azacitidine | Approved (see text) |
| Decitabine | Approved (see text) | ||
| Rationally designed novel inhibitors | Preclinical and clinical94,95 | ||
| Regulator of methylation | IDH1, IDH2 | Inhibitors of mutant IDH1/2 | Clinical trials ongoing with compounds including IDH305 (ClinicalTrials.gov identifier: NCT02381886; targeted at IDH1 R132 mutation), AG-221 (NCT01915498; targeted at mutant IDH2), AG-120 (NCT02074839; targeted at mutant IDH1) |
| Histone lysine acetyltransferase | CREBBP (CBP) | CREBBP inhibitor | Preclinical96 |
| EP300 (p300) | EP300 inhibitor | Preclinical97 | |
| Histone deacetylase | HDACs | HDAC inhibitors | Several clinical trials ongoing, often in combination with other treatment modalities (eg, with DNMT inhibitors [examples ClinicalTrials.gov identifiers NCT01617226 and NCT00867672], conventional chemotherapy [example NCT01802333], or in conjunction with allogeneic stem cell transplantation [examples NCT01451268 and http://www.hovon.nl/studies/studies-per-ziektebeeld/aml.html?action=showstudie&studie_id=104&categorie_id=4]) |
| Histone acetyl reader | Bromodomain containing proteins (BET proteins) | BET inhibitors | Several clinical trials ongoing with compounds including OTX-015 (ClinicalTrials.gov identifier: NCT01713582), CPI-0610 (NCT02158858), TEN-010 (NCT02308761), GSK525762 (NCT01943851) |
| Histone lysine methyltransferase | EZH2 | EZH2 inhibitors | Preclinical98,99 |
| MLL-complexes | DOT1L inhibitors | Clinical trial with compounds including EPZ-5676 (ClinicalTrials.gov identifier: NCT01684150) | |
| Inhibitors of MLL-Menin interface | Preclinical100 | ||
| Inhibitors of MLL-LEDGF interface | Preclinical101 | ||
| Histone lysine demethylase | LSD1 | LSD1 inhibitors | Clinical trials with compounds including GSK2879552 (ClinicalTrials.gov identifier: NCT02177812) and tranylcypromine in combination with tretinoine (NCT02261779) |
| Jumonji family of KDMs | Small molecular inhibitors competitive for 2-oxoglutarate | Preclinical102,103 | |
| Histone arginine methyltransferase | PRMTs | PRMT inhibitors | Preclinical104,105 |
| Class of epigenetic regulator . | Target . | Compound . | Phase of development . |
|---|---|---|---|
| DNA methyltransferase | DNMTs | Azacitidine | Approved (see text) |
| Decitabine | Approved (see text) | ||
| Rationally designed novel inhibitors | Preclinical and clinical94,95 | ||
| Regulator of methylation | IDH1, IDH2 | Inhibitors of mutant IDH1/2 | Clinical trials ongoing with compounds including IDH305 (ClinicalTrials.gov identifier: NCT02381886; targeted at IDH1 R132 mutation), AG-221 (NCT01915498; targeted at mutant IDH2), AG-120 (NCT02074839; targeted at mutant IDH1) |
| Histone lysine acetyltransferase | CREBBP (CBP) | CREBBP inhibitor | Preclinical96 |
| EP300 (p300) | EP300 inhibitor | Preclinical97 | |
| Histone deacetylase | HDACs | HDAC inhibitors | Several clinical trials ongoing, often in combination with other treatment modalities (eg, with DNMT inhibitors [examples ClinicalTrials.gov identifiers NCT01617226 and NCT00867672], conventional chemotherapy [example NCT01802333], or in conjunction with allogeneic stem cell transplantation [examples NCT01451268 and http://www.hovon.nl/studies/studies-per-ziektebeeld/aml.html?action=showstudie&studie_id=104&categorie_id=4]) |
| Histone acetyl reader | Bromodomain containing proteins (BET proteins) | BET inhibitors | Several clinical trials ongoing with compounds including OTX-015 (ClinicalTrials.gov identifier: NCT01713582), CPI-0610 (NCT02158858), TEN-010 (NCT02308761), GSK525762 (NCT01943851) |
| Histone lysine methyltransferase | EZH2 | EZH2 inhibitors | Preclinical98,99 |
| MLL-complexes | DOT1L inhibitors | Clinical trial with compounds including EPZ-5676 (ClinicalTrials.gov identifier: NCT01684150) | |
| Inhibitors of MLL-Menin interface | Preclinical100 | ||
| Inhibitors of MLL-LEDGF interface | Preclinical101 | ||
| Histone lysine demethylase | LSD1 | LSD1 inhibitors | Clinical trials with compounds including GSK2879552 (ClinicalTrials.gov identifier: NCT02177812) and tranylcypromine in combination with tretinoine (NCT02261779) |
| Jumonji family of KDMs | Small molecular inhibitors competitive for 2-oxoglutarate | Preclinical102,103 | |
| Histone arginine methyltransferase | PRMTs | PRMT inhibitors | Preclinical104,105 |