Table 2.
Overview of epigenetic inhibitors currently in clinical trials for cancer therapies.
| Inhibitor | Mechanism of Action | Functional Molecule or Chemical Group | Examples | CAS | Clinical Trials | ||||
|---|---|---|---|---|---|---|---|---|---|
| Phase Studies | Conditions | ||||||||
| I | II | III | IV | ||||||
| DNMTi | Nucleoside analogs: Cytidine analogs incorporate into DNA instead of cytidine, covalently linking the enzyme and leading to DNMT degradation | Cytidine | Azacytidine | 320-67-2 | 272 | 350 | 58 | 7 | MDS, CML, AML, glioma, prostate cancer, pancreatic cancer, ovarian cancer, metastatic melanoma. |
| Decitabine | 2353-33-5 | 189 | 240 | 51 | 7 | CML, AML, MDS, prostate cancer, thyroid cancer. | |||
| Guadecitabine | 929901-49-5 | 15 | 23 | 3 | 0 | AML, MDS, HCC, CMML, ovarian cancer, urothelial carcinoma, colorectal cancer, peritoneal cancer | |||
| 5-fluoro-2’-deoxycytidine | 10356-76-0 | 3 | 1 | 0 | 0 | AML, MDS, Head and Neck Neoplasms, Lung Neoplasms, Urinary Bladder Neoplasms, Breast Neoplasms | |||
| 4’-thio-2’-deoxycytidine | 134111-30-1 | 2 | 0 | 0 | 0 | Currently establishing the safety, tolerability, and MTD in patients with refractory solid tumors. | |||
| Non-nucleoside inhibitors either block the DNMTs enzyme catalytic site, interact with enzyme recognition of target sequences or are SAM cofactor competitors. | S-Adenosyl methionine | Sinefungin | 58944-73-3 | 0 | 0 | 0 | 0 | NA | |
| Hydrazine | Hydralazine | 86-54-4 | 6 | 16 | 13 | 12 | ovarian cancer, cervical cancer, refractory solid tumors, breast cancer. | ||
| Flavonoids (C6-C3-C6) | Epigallocatechin-3-gallate | 989-51-5 | 18 | 44 | 14 | 3 | Adenocarcinoma of the prostate, head and neck cancer, colon cancer, pancreatic cancer, breast cancer, lung cancer, bladder cancer, colorectal cancer, prostate cancer. | ||
| HDACi | HDACi are molecules capable of Zinc trapping that bind to the zinc-containing catalytic domain of HDACs and supress their deacetylase enzymatic activity | Hydroxamic Acid | Vorinostat | 149647-78-9 | 165 | 149 | 9 | 0 | Rhabdomyosarcoma, Leiomyosarcoma, Lymphoma, melanoma, Lung carcinoma, lung cancer, head and neck cancer, leukemia, breast cancer, MDS, ovarian cancer, glioblastoma, pancreatic cancer, breast cancer. |
| Trichostatin A | 58880-19-6 | 1 | 0 | 0 | 0 | Relapsed or Refractory Hematologic Malignancies | |||
| Belinostat | 866323-14-0 | 32 | 25 | 0 | 0 | MDS, Non-Hodgkin lymphona, mantle cell lymphoma, diffuse large B-cell lymphoma, breast cancer, ovarian cancer, lung cancer, glioblastoma, AML, ATLL, bladder cancer, liver cancer, | |||
| Panobinostat | 404950-80-7 | 87 | 78 | 7 | 1 | AML, MDS, lung cancer, gliosarcoma, prostate cancer, multiple myeloma, CMML, breast cancer, pancreatic cancer. | |||
| dacinostat | 404951-53-7 | 0 | 0 | 0 | 0 | NA | |||
| givinostat | 497833-27-9 | 5 | 15 | 2 | 0 | chronic lymphocytic leukemia, multiple myeloma, hodgkin’s lymphoma. | |||
| Benzamides | Entinostat | 209783-80-2 | 40 | 37 | 2 | 0 | breast cancer, prostate adenocarcinoma, renal cell carcinoma, lymphoma, MDS, melanoma, lung cancer, AML, colorectal cancer, pancreatic cancer | ||
| mocetinostat | 726169-73-9 | 14 | 15 | 0 | 0 | urothelial carcinoma, Hodgkin lymphoma, Head and Neck cancer, MDS, lung cancer, melanoma. | |||
| Thiols | Romidepsin | 128517-07-7 | 55 | 57 | 5 | 0 | T cell lymphoma, glioma, multiple myeloma, CTCL, leukemia, astrocytoma, pancreatic cancer, lung cancer, thyroid cancer, prostate cancer, male breast cancer, renal cancer, bladder cancer. | ||
| Carboxylic Acids | Valproic acid | 1069-66-5 | 85 | 115 | 90 | 89 | AML, MDS, Head and Neck cancer, SCC, glioma, bladder cancer, sarcoma, glioblastoma, leukemia, breast cancer, lung cancer. | ||
| Butyric Acid | 107-92-6 | 1 | 3 | 2 | 0 | schyzofrenic disorders | |||
| Phenylbutiric Acid | 1821-12-1 | 20 | 30 | 3 | 2 | colon cancer, leukemia, gastric cancer, MDS. | |||
| Pivanex | 122110-53-6 | 1 | 3 | 0 | 0 | melanoma, lung cancer, leukemia. | |||
| SIRTi are small molecules, many of them recently discovered by cell-based screening assays, with multiple inhibition mechanisms including reactivity with chemical intermediates, non-competitive inhibition with substrate and uncompetitive inhibition with NAD+. | NAD+ | Nicotin | 54-11-5 | 0 | 0 | 0 | 0 | NA | |
| beta-naphtol | sirtinol | 410536-97-9 | 0 | 0 | 0 | 0 | NA | ||
| splitomicin | 1384339 | 0 | 0 | 0 | 0 | NA | |||
| salermide | 1105698-15-4 | 0 | 0 | 0 | 0 | NA | |||
| cambinol | 14513-15-6 | 0 | 0 | 0 | 0 | NA | |||
| indole | EX-527 | 49843-98-3 | 0 | 1 | 0 | 0 | Endometriosis | ||
| oxyndole | 59-48-3 | 0 | 0 | 0 | 0 | NA | |||
| urea | suramin | 129-46-4 | 8 | 12 | 3 | 0 | lung cancer, breast cancer, adrenocortical carcinoma, renal cancer, prostate cancer, bladder cancer, multiple myeloma, head and neck cancer. | ||
| thiourea | tenovin | 380315-80-0 | 0 | 0 | 0 | 0 | NA | ||
| HMTi | HKMTi are SAM like molecules and molecules that directly inhibits the enzyme S-adenosyl-L-homocysteine hydrolase or interact with the cofactor binding pocket of KMTs | S-Adenosyl methionine | Sinefungin | 58944-73-3 | 0 | 0 | 0 | 0 | NA |
| EPZ004777 | 1338466-77-5 | 0 | 0 | 0 | 0 | NA | |||
| EPZ-5676 | 1380288-87-8 | 4 | 2 | 0 | 0 | AML, MDS, leukemia | |||
| EPZ004777 | 1338466-77-5 | 0 | 0 | 0 | 0 | NA | |||
| Valemetostat | 1809336-39-7 | 1 | 1 | 0 | 0 | leukemia, lymphoma, prostate cancer, renal cancer. | |||
| tazemetostat | 1403254-99-8 | 11 | 10 | 2 | 0 | B cell lymphoma, prostate cancer, mesothelioma, Non Hodgkin lymphoma, tissue sarcoma, Bladder cancer, sinonasal carcinoma, follicular lymphoma. | |||
| Most HRMT inhibitors are molecules which occupy and inhibit the SAM pocket, the substrate pocket, or both. | S-Adenosyl methionine | GSK3326595 | 1616392-22-3 | 2 | 0 | 0 | 0 | neoplasms | |
| HDMi | HDM inhbitors are molecules that inhibit monomine oxidases family of enzymes or that are substrate mimics (lysine analogs). | Arylalkylamines | Phenelzine | 51-71-8 | 4 | 2 | 0 | 0 | breast cancer, prostate cancer. |
| Tranylcypromine | 155-09-9 | 6 | 3 | 1 | 3 | AML, MDS | |||
| Pargyline | 306-07-0 | 0 | 0 | 0 | 0 | NA | |||
| Lysine analogs | propylhydrazine | 5039-61-2 | 0 | 0 | 0 | 0 | NA | ||
| JmjC inhibitors are derivates of 2OG, hydroxamic acids, catechols and flavonoids. | 2-oxoglutarate | N-oxalylglicine | 5262-39-5 | 0 | 0 | 0 | 0 | NA | |
| Hydroxamic Acid | Methylstat | 1310877-95-2 | 0 | 0 | 0 | 0 | NA | ||
| Catechols | Hematoxylin | 517-28-2 | 0 | 0 | 0 | 0 | NA | ||
| Caffeic acid | 331-39-5 | 3 | 1 | 3 | 1 | esophagus cancer | |||
| Flavonoids (C6-C3-C6) | Myricetin | 529-44-2 | 0 | 0 | 0 | 0 | NA | ||
| Baicalein | 491-67-8 | 0 | 2 | 0 | 0 | Influenza | |||
| Epigallocatechin-3-gallate | 989-51-5 | 18 | 44 | 14 | 3 | Adenocarcinoma of the prostate, head and neck cancer, colon cancer, pancreatic cancer, breast cancer, lung cancer, bladder cancer, colorectal cancer, prostate cancer. | |||
| BETi | BET inhibitors are derivates of benzodiazepines that take up the hydrophobic región of BET enzymes which binds acetylated lysines. | Thienotriazolodiazepines | JQ1 | 1268524-70-4 | 0 | 0 | 0 | 0 | NA |
| CPI-203 | 1446144-04-2 | 0 | 0 | 0 | 0 | NA | |||
| OTX015 | 202590-98-5 | 5 | 2 | 0 | 0 | AML, glioblastoma, breast cancer, lung cancer, prostate cancer. | |||
| Benzodiazepines | CPI-0610 | 1380087-89-7 | 3 | 2 | 0 | 0 | Myeloma, lymphoma, leukemia, MDS. | ||
| Molibresib | 1260907-17-2 | 2 | 1 | 0 | 0 | lymphoma, NUT carcinoma, | |||