Table 1 Emerging epigenetic drugs for AML treatment

From: Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Compound

Target

Mechanism

Development

DOT1L inhibitor

H3K79 methyltransferase DOT1L

Depletion of H3K79me2, leading to repression of MLL fusion targets

Preclinical EPZ477759

Phase I clinical trial EPZ5676 (NCT01684150, MLL leukaemia)

PRMT1 inhibitor

H4R3 methyltransferase PRMT1

Depletion of H4R3me2a, leading to repression of MLL fusion targets

Preclinical AMI-40842

EZH2 inhibitor

H3K27 methyltransferase EZH2

Suppression of H3K27me3, leading to de-repression of polycomb targets (for example, CDKN2A, TXNIP)

Preclinical DZNep61 UNC199963

MOA inhibitor TCP, TCP derivatives

H3K4 demethylase KDM1A (LSD1)

Unknown mechanism in AML enhances H3K4me1/2?

Clinical trials GSK2879552 (NCT02177812, refractory AML) ORY-1001 (EudraCT 2013-002447-29, refractory acute leukaemia)

Non-MOA inhibitor

H3K4 demethylase KDM1A (LSD1)

Blocking the interaction of LSD1 and CoREST

Preclinical SP250968

KDM4C inhibitor

H3K9 demethylase KDM4C (JMJD2C

Increase in H3K9me3, leading to repression of MLL fusion or MOZ-TIF2 targets

Preclinical SD7042

BET inhibitor

Bromodomain-containing proteins, BRD family

Displacement of BRD family from chromatin

Phase I clinical trials OTX015 (NCT01713582, acute leukaemia and various haematological malignancies) CPI-0610 (NCT02158858, acute leukaemia and MDS) GSK525762 (NCT01943851, relapsed haematological malignancies)

  1. Abbreviations: AML, acute myeloid leukaemia; LSD1, lysine-specific demethylase; MDS, myelodysplastic syndrome; MLL, mixed lineage leukaemia; PRMT1, protein arginine methyltransferases.
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