A Novel and Potent EZH1/2 Dual Inhibitor HM97594 for the Treatment of Hematological Malignancies

In mammals, either enhancer of zeste homologue 2 (EZH2) or its homolog EZH1 functions as the catalytic subunit of polycomb repressive complex 2 (PRC2), and plays an essential role for the maintenance of transcriptional repression by the trimethylation of histone H3 lysine 27 (H3K27me3). Hyperinduction of H3K27me3 mediated by EZH2 overexpression or EZH2 gain-of-function (GOF) mutation (e.g. Y641, A677 and A687) has been associated with lymphoma and myeloma progression. Many publications suggest that suppressing PRC2 activity by EZH2 inhibition is a potential therapeutic target for hematological malignancies. Up to date, there are known a few EZH2 selective inhibitors with showing anti-tumor activity in some preclinical and clinical studies.

However, the inhibition of EZH2 can complementarily induce EZH1 activation, which reactivates PRC2 function in turn. Therefore, dual inhibition of EZH1 and EZH2 could give more effective than EZH2 inhibition alone in blocking PRC2 function as an anti-cancer therapy. Herein, we introduce a novel EZH1/2 dual inhibitor, HM97594, which simultaneously inhibits the methyltransferase activity of wild-type EZH1 as well as wild-type and GOF mutant EZH2 at nanomolar concentrations.

HM97594 potently repressed trimethylation of H3K27 in lymphoma and myeloma cell lines. As a result, HM97594 showed broader and stronger activities than EZH2 selective inhibitors in in vitro studies of inhibiting the proliferation of various hematological cancer cell lines. HM97594 induced the differentiation of DLBCL to plasma cells with an increment of cell lineage specific markers (e.g. PRDM1, IRF4 and CD38) and decreased the colony forming ability. Also, HM97594 caused cell cycle G0/1 arrest and apoptosis in KARPAS-422 cells harboring EZH2 Y641 GOF mutation.

In addition, HM97594 showed potent antitumor activity in KARPAS-422 lymphoma cell xenograft mouse model. Once daily orally administered HM97594 greatly inhibited tumor growth in a dose-dependent manner without body weight loss compared to the known EZH2 inhibitor.

Collectively, it was demonstrated in the present studies that HM97594, EZH1/2 dual inhibitor, has promising potential as an anticancer drug for patients with subtypes of hematological malignancies. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate.