Table 1 Epigenetic modulators in cancer
Drug | Target | Clinical status | Indication | References |
|---|---|---|---|---|
DNMT inhibitors | ||||
Azacitidine | Inhibit DNMT (act as nucleoside analog) | FDA-approved | MDS | |
Decitabine | Inhibit DNMT (act as nucleoside analog) | FDA-approved | MDS | |
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 | |
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 | |
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 | |
Pracinostat | Inhibitor of Class I and II HDACs | Phase 2 (NCT01112384, NCT01075308) | Translocation-associated recurrent/metastatic sarcomas, metastatic prostate cancer | |
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 | |
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) | |
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 | |
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 | |
BIX01294 | Inhibit G9a (substrate-competitive) | Not in trial | Breast cancer, colon cancer | |
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 | |
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 | |
I-BET151 (GSK1210151A) | Interfere with binding of BET proteins to acetylated histones | Not in trial | MLL fusion leukemia, medulloblastoma | |
OTX015 | Interfere with binding of BET proteins to acetylated histones | Phase 1 (NCT01713582) | Hematological malignancies | |
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] |