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A Novel Inhibitor for the Treatment of B-Cell Lymphomas

The new inhibitor might prove to be more efficacious than the current Tazemetostat.

The polycomb repressive complex 2 (PRC2) is a protein complex important in regulating the repressive states of thousands of developmental genes. The enhancer of zeste homologue 2 (EZH2) is an enzymatic subunit of the protein complex and has been found to be overexpressed in haematologic malignancies and solid tumours. The drug Tazemetostat is the first selective inhibitor of EZH2 wild-type and mutants approved by the US Food and Drug Administration. However, despite its success, there is still a need for greater varieties of EZH2 inhibitors to aid preclinical mechanistic and clinical pathological studies.

Now, a team of researchers led by Professor Liu Qingsong from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences has discovered a potent and selective inhibitor of EZH2 that has displayed the potential to treat B-cell lymphomas.

By building on Tazemetostat, which had previously displayed B-cell lymphoma efficacies in preclinical models, the researchers used a focused medicinal chemistry approach guided by computer-aided drug design and derived their novel inhibitor IHMT-EZH2-115.

According to the biochemical assay, the novel inhibitor IHMT-EZH2-115 was highly potent to both wild-type and mutant EZH2, and exhibited good selectivity over a broad range of epigenetic targets. It also displayed selective antiproliferative effects against cells carrying various heterozygous EZH2 mutations.

To test for potential drug-drug interactions, the researchers tested their novel inhibitor against a panel of the most important metabolic enzymes. The data obtained suggest a low possibility for drug-drug interactions. Their inhibitor was also investigated for potential heart toxicity, where a very weak inhibitory activity was observed; this result fell under a safe range.

With favourable pharmacokinetic properties, the novel inhibitor IHMT-EZH2-115 was assessed for its anti-tumour effects in two xenograft mice models of B-cell lymphoma. By comparing the novel inhibitor with Tazemetostat, it was found that the team’s novel inhibitor exhibited better efficacy than Tazemetostat at an oral dosage of 200mg/kg BID in the two xenograft mice models.

All these results suggest that the novel inhibitor IHMT-EZH2-115 might be a potential clinical development candidate for EZH2 mutant-driven tumours. [APBN]

Source: Zhou et al. (2021). Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas. Journal of Medicinal Chemistry.