A potent and selective enhancer of zeste homolog 2 (EZH₂) inhibitor IHMT-EZH₂-115 was recently discovered by researchers led by Prof. LIU Qingsong from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences for the treatment of B-cell lymphomas.

EZH₂ is the enzymatic subunit of polycomb repressive complex 2. As a therapeutic target for the treatment of cancer, it has been extensively studied. Overexpression or mutation of EZH₂ has been identified in hematologic malignancies and solid tumors. EPZ6438 (Tazemetostat) is the first selective inhibitor of EZH₂ wild-type and mutants approved by the Food and Drug Administration (FDA). Despite the clinical success, the diversity of EZH₂ inhibitors is still highly demanded for both the preclinical mechanistic and clinical pathological studies.

In this study, starting from EPZ6438 which exhibited anti-B-cell lymphoma efficacies in the preclinical models, the researchers obtained IHMT-EZH₂-115 using a focused medicinal chemistry approach guided by computer-aided drug design.

According to the biochemical assay, IHMT-EZH₂-115 was highly potent to both EZH₂ wild-type and mutants. Meanwhile, it showed high selectivity over a broad range of histone methyltransferases. Furthermore, the inhibitor exhibited excellent antiproliferative activities against cells carrying the heterozygous EZH2 A677G, Y641F, Y641N, and Y641S mutations.

In vivo, IHMT-EZH₂-115 exhibited favorable pharmacokinetic characteristics for oral administration and demonstrated dose-dependent antitumor efficacies in two xenograft mouse models of diffuse large B-cell lymphoma cell lines harboring EZH₂ mutations, Pfeiffer (EZH₂ A677G) and Karpas-422 (EZH₂ Y641N).

These results indicate that IHMT-EZH₂-115 may be a potential clinical development candidate for the EZH₂ mutant driven tumors.

 Anti-tumor efficacy evaluation of IHMT-EZH₂-115 in xenograft mouse models (Image by ZHOU Bin)