Selective small molecule targeting of KDM4 as a therapeutic strategy to reduce proliferation of acute myeloid leukaemia

Acute myeloid leukaemia (AML) is an aggressive disease with poor survival and high relapse rates. Coupled with the complex mutational burden observed, there is an unmet clinical need for more targeted therapies. Epigenetic therapies have shown promise both as monotherapy and in combination strategies and specifically histone lysine demethylase, KDM4A (Lysine demethylase 4), plays a role in the maintenance of AML, with its short hairpin (shRNA) knockdown sufficient to target leukaemia cells while sparing normal haemopoietic cells. In this study, we utilised a novel KDM4 inhibitor based on the structure of IOX-1, the most characterised inhibitor of the 2-oxygenase enzymes to which the KDM4 family belong, to investigate further the role of KDM4A in AML. Our compound induced AML cell death with cell cycle arrest, failure of colony formation and transcriptomic changes in metabolism, transcription control and response to stress. With known roles for KDM4A family members in deoxyribonucleic acid (DNA) damage response repair pathways, inhibition of KDM4A increased accrual of double strand DNA breaks. Hence, we demonstrated KDM4i sensitisation of leukaemia cells to inhibitors of DNA damage pathways such as poly-ADP ribose polymerase (PARP) inhibitor, olaparib, suggesting future clinical evaluation of KDM4A and other key components in DNA damage/response signalling pathways as potential therapeutic vulnerabilities in AML.