Novel epigenetic-targeted pharmacologic agents in preclinical development in the treatment of myeloid malignancies
| Target . | Rationale . | Stage of clinical development . |
|---|---|---|
| BET family of bromodomain containing proteins (BRD2, BRD3, BRD4, and BRDt) | Inhibition of BET bromodomains has been repeatedly shown to have therapeutic efficacy in preclinical models of AML (both MLL translocated and MLL wild-type AML).74,75 A single underlying basis for this efficacy is not entirely clear but it is possibly related to downregulation of MYC transcription following BET inhibition and/or to inhibition of transcriptional elongation. | Phase 1 study of the BRD2/3/4 inhibitor OTX015 in patients with hematologic malignancies is ongoing. |
| DOT1L | Most MLL translocations result in recruitment of the histone 3H lysine 79 methyltransferase DOT1L (reviewed in Krivtsov et al44 ) and recruitment of DOT1L has been shown to be critical for the transforming properties of MLL fusion proteins.76 | Phase 1 and expanded cohort study of EPZ-5676 in advanced hematologic malignancies, including acute leukemia with MLL rearrangements. |
| IDH1/IDH2 | Recurrent gain-of-function mutations in IDH1 and IDH2 result in the production of 2-HG38,39 and both the presence of the mutant forms of IDH1/229,31,41 as well as the presence of 2-HG alone31 has been shown to be transforming for myeloid hematopoietic cells. Thus, mutant-selective inhibitors of IDH1 and IDH2 are in preclinical development.42 | Preclinical studies on the therapeutic potential of mutant IDH1/2 pharmacologic inhibition are ongoing.42 |
| EZH2 | Despite the fact that somatic deletions and mutations of EZH2 are present in patients with myeloid malignancies,77 genetic deletion of EZH2 has been shown to impair the oncogenicity of MLL-AF9 AML cells.62-64 | Preclinical studies on the therapeutic potential of EZH2 pharmacologic inhibition54,55 in the context of MLL wild-type and translocated AML are ongoing. |
| LSD1 | Downregulating LSD1 by RNA interference or pharmacologic inhibition with tranylcypromine analogs selectively targeted MLL translocated leukemic cells by inducing their differentiation in one study.58 In another study, combining LSD1 inhibition with ATRA resulted in terminal differentiation and abrogation of leukemogenesis of AML cell lines and primary AML samples (regardless of presence of MLL translocation).56 | Preclinical studies of tranylcypromine and compounds derived from it are ongoing. In addition, development of more potent and selective LSD1 inhibitors are in development.57,59,78 |
| UTX/JMJD3 | The recurrent presence of mutations which result in loss of H3K27me3 in myeloid malignancies (including ASXL1,51 EZH2,77 SUZ12,79 and EED79 deletions and somatic mutations) suggest a rationale for inhibiting demethylation of H3K27 in these disorders. | Preclinical studies on the therapeutic potential of UTX/JMJD3 pharmacologic inhibition80 in human malignancies are ongoing. |
| Target . | Rationale . | Stage of clinical development . |
|---|---|---|
| BET family of bromodomain containing proteins (BRD2, BRD3, BRD4, and BRDt) | Inhibition of BET bromodomains has been repeatedly shown to have therapeutic efficacy in preclinical models of AML (both MLL translocated and MLL wild-type AML).74,75 A single underlying basis for this efficacy is not entirely clear but it is possibly related to downregulation of MYC transcription following BET inhibition and/or to inhibition of transcriptional elongation. | Phase 1 study of the BRD2/3/4 inhibitor OTX015 in patients with hematologic malignancies is ongoing. |
| DOT1L | Most MLL translocations result in recruitment of the histone 3H lysine 79 methyltransferase DOT1L (reviewed in Krivtsov et al44 ) and recruitment of DOT1L has been shown to be critical for the transforming properties of MLL fusion proteins.76 | Phase 1 and expanded cohort study of EPZ-5676 in advanced hematologic malignancies, including acute leukemia with MLL rearrangements. |
| IDH1/IDH2 | Recurrent gain-of-function mutations in IDH1 and IDH2 result in the production of 2-HG38,39 and both the presence of the mutant forms of IDH1/229,31,41 as well as the presence of 2-HG alone31 has been shown to be transforming for myeloid hematopoietic cells. Thus, mutant-selective inhibitors of IDH1 and IDH2 are in preclinical development.42 | Preclinical studies on the therapeutic potential of mutant IDH1/2 pharmacologic inhibition are ongoing.42 |
| EZH2 | Despite the fact that somatic deletions and mutations of EZH2 are present in patients with myeloid malignancies,77 genetic deletion of EZH2 has been shown to impair the oncogenicity of MLL-AF9 AML cells.62-64 | Preclinical studies on the therapeutic potential of EZH2 pharmacologic inhibition54,55 in the context of MLL wild-type and translocated AML are ongoing. |
| LSD1 | Downregulating LSD1 by RNA interference or pharmacologic inhibition with tranylcypromine analogs selectively targeted MLL translocated leukemic cells by inducing their differentiation in one study.58 In another study, combining LSD1 inhibition with ATRA resulted in terminal differentiation and abrogation of leukemogenesis of AML cell lines and primary AML samples (regardless of presence of MLL translocation).56 | Preclinical studies of tranylcypromine and compounds derived from it are ongoing. In addition, development of more potent and selective LSD1 inhibitors are in development.57,59,78 |
| UTX/JMJD3 | The recurrent presence of mutations which result in loss of H3K27me3 in myeloid malignancies (including ASXL1,51 EZH2,77 SUZ12,79 and EED79 deletions and somatic mutations) suggest a rationale for inhibiting demethylation of H3K27 in these disorders. | Preclinical studies on the therapeutic potential of UTX/JMJD3 pharmacologic inhibition80 in human malignancies are ongoing. |
Preclinial and clinical trials involving novel DNA methyltransferase inhibitors and HDAC inhibitors are not mentioned. BET, bromodomain and extra-terminal; HDAC, histone deacetylase.