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