A potent and selective enhancer of zeste homolog 2 (EZH 2 ) inhibitor IHMT-EZH 2 -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.
EZH 2 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 EZH 2 has been identified in hematologic malignancies and solid tumors. EPZ6438 (Tazemetostat) is the first selective inhibitor of EZH 2 wild-type and mutants approved by the Food and Drug Administration (FDA). Despite the clinical success, the diversity of EZH 2 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-EZH 2 -115 using a focused medicinal chemistry approach guided by computer-aided drug design.
According to the biochemical assay, IHMT-EZH 2 -115 was highly potent to both EZH 2 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-EZH 2 -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 EZH 2 mutations, Pfeiffer (EZH 2 A677G) and Karpas-422 (EZH 2 Y641N).
These results indicate that IHMT-EZH 2 -115 may be a potential clinical development candidate for the EZH 2 mutant driven tumors.
Journal of Medicinal Chemistry
https://doi.org/10.1021/acs.jmedchem.1c01154
Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas
19-Oct-2021