Table 1.
Epigenetic modulators in cancer
| Drug | Target | Clinical status | Indication | References |
|---|---|---|---|---|
| DNMT inhibitors | ||||
| Azacitidine | Inhibit DNMT (act as nucleoside analog) | FDA-approved | MDS | [277, 278] |
| Decitabine | Inhibit DNMT (act as nucleoside analog) | FDA-approved | MDS | [115, 277] |
| SGI-110 | Inhibit DMNT by incorporating into guanine nucleotide | Phase 3 (NCT02348489 Phase 1/2 (NCT01261312, NCT02197676) Phase 2 (NCT01752933) Phase 1/2 (NCT01696032) |
AML MDS, AML Advanced HCC Platinum-resistant recurrent ovarian cancer |
[279–281] |
| HDAC inhibitors | ||||
| Vorinostat | Inhibitor of Class I and II HDACs | FDA-approved | Cutaneous T cell lymphoma | [135] |
| Romidepsin | Inhibitor of Class I HDACs | FDA-approved | Cutaneous T cell lymphoma | [136] |
| Panobinostat | Pan-HDAC inhibitor | Phase 3 (NCT01034163) Phase 2/3 (NCT00425555) |
Hodgkin’s lymphoma Cutaneous T cell lymphoma |
[282, 283] |
| Entinostat | Inhibitor of Class I HDACs | Phase 2 (NCT00866333) Phase 1/2 (NCT01038778) |
Hodgkin’s lymphoma Clear cell renal cell carcinoma, metastatic renal cell cancer |
[284] |
| Belinostat | Inhibitor of Class I and II HDACs | Phase 2 (NCT00357032) Phase 2 (NCT00274651) Phase 2 (NCT00301756) |
Relapsed/refractory AML or older patients with newly diagnosed AML Recurrent/refractory cutaneous and peripheral T cell lymphomas Ovarian cancer |
[285–287] |
| Pracinostat | Inhibitor of Class I and II HDACs | Phase 2 (NCT01112384, NCT01075308) |
Translocation-associated recurrent/metastatic sarcomas, metastatic prostate cancer | [288, 289] |
| Givinostat | Inhibitor of Class I and II HDACs | Phase 2 (NCT01761968) |
Chronic myeloproliferative neoplasms | [290] |
| Valproic acid | Inhibitor of Class I and II HDACs | Phase 2 (NCT01900730) |
Breast cancer | [163, 291] |
| HMT inhibitors | ||||
| EPZ-5676 | Inhibit DOT1L methyltransferase (H3K79) activity by competing with SAM | Phase 1 (NCT02141828, NCT01684150) |
MLL-fusion leukemia, AML, acute lymphocytic/lymphoblastic leukemia, MDS, myeloproliferative disorders | [182] |
| DZNep | Inhibit HMT activity of EZH2 via inhibiting S-adenosylhomocysteine (SAH) hydrolase | Not in trial | Breast cancer, prostate cancer, glioblastoma multiforme (GBM) |
[193, 292, 293] |
| E7438 (EPZ-6438) | Inhibit HMT activity of EZH2 by competing with co-factor S-adenosyl-methionine (SAM) | Phase 2 (NCT02860286, NCT02601950) |
Malignant mesothelioma, rhabdoid tumors, synovial sarcoma, epitheloid sarcoma | [196] |
| GSK2816126 (GSK126) | Inhibit HMT activity of EZH2 by competing with co-factor S-adenosyl-methionine (SAM) | Phase 1 (NCT02082977) |
Relapsed/refractory DLBCL, transformed follicular lymphoma, multiple myeloma, non-Hodgkin’s lymphoma, solid tumors | [198, 199] |
| CPI-1205 | Inhibit HMT activity of EZH2 by competing with co-factor S-adenosyl-methionine (SAM) | Phase 1 (NCT02395601) |
B-cell lymphoma | [294] |
| Chaetocin | Inhibit SUV39H1 | Not in trial | HCC, multiple myeloma | [216, 218] |
| BIX01294 | Inhibit G9a (substrate-competitive) | Not in trial | Breast cancer, colon cancer | [209, 212] |
| UNC0638 | Inhibit G9a (substrate-competitive) | Preclinical | Breast cancer | [213] |
| UNC0642 | Inhibit G9a (substrate-competitive) | Preclinical | Pancreatic cancer | [214] |
| HDM inhibitors | ||||
| Tranylcypromine | Irreversible inhibitor of LSD1 | Phase 1 (NCT02273102, NCT02717884) Phase1/2 (NCT02261779) |
AML, MDS AML |
[226] |
| ORY-1001 | Irreversible inhibitor of LSD1 | Phase 1 | AML | [227] |
| GSK2879552 | Irreversible inhibition of LSD1 activity by modifying its cofactor FAD | Phase 1 (NCT02034123, NCT02177812) |
Small cell lung cancer, AML |
[231] |
| GSK-J4 | Inhibit UTX | Not in trial | T-cell acute lymphoblastic leukemia (T-ALL) | [295] |
| BET inhibitors | ||||
| I-BET762 (GSK525762A) | Interfere with binding of BET proteins to acetylated histones | Phase 1 (NCT01587703, NCT01943851) |
Solid tumors, relapsed refractory haematological malignancies | [243, 244] |
| JQ1 | Interfere with binding of BET proteins to acetylated histones (greatest specificity for BRD3 and BRD4) | Not in trial | NUT midline carcinoma (NMC), multiple myeloma, AML, Burkitt’s lymphoma, DLBCL | [239, 240, 296, 297] |
| I-BET151 (GSK1210151A) | Interfere with binding of BET proteins to acetylated histones | Not in trial | MLL fusion leukemia, medulloblastoma | [298, 299] |
| OTX015 | Interfere with binding of BET proteins to acetylated histones | Phase 1 (NCT01713582) |
Hematological malignancies | [248, 297] |
| CPI-203 | Interfere with binding of BET proteins to acetylated histones | Not in trial | Lymphoma | [300] |
| CPI-0610 | Interfere with binding of BET proteins to acetylated histones | Phase 1 (NCT02157636, NCT01949883, NCT02158858) |
Acute leukaemia, MDS, myelodysplastic/myeloproliferative neoplasms, lymphoma, multiple myeloma | [301] |