Ruihua Xu commented, "Targeting PRC2 complex proteins, especially the EED, may be an effective mechanistic approach for treating cancer patients with certain genetic profiles. Preliminary data showed that APG-5918 has in vitro antiproliferative activity in various tumor cell lines and antitumor activity in patient-derived xenograft (PDX)/cell line-derived xenograft (CDX) models of EZH1-mutant B-cell non-Hodgkin lymphoma, IN1-negative malignant rhabdoid tumor, BAP1-mutant mesothelioma and prostate cancer. APG-5918 can selectively bind to the H3K27me3 domain of the EED protein, leading to the conformational changes to H3K27me3's binding pockets in the EED protein, which can then block EED from interacting with the histone methyltransferase EZH2. APG-5918 can regulate the epigenetics of tumors and the tumor microenvironment, and therefore has broad therapeutic potential for the treatment of hematologic malignancies, solid tumors, and nononcologic conditions. 1 Therefore, allosteric targeting of EED has in recent years gained a great deal of traction as a promising approach for inhibiting the replacement of inactivated PRC2.ĭiscovered and developed by Ascentage Pharma, APG-5918 is an orally active, potent, selective, small-molecule EED inhibitor with high binding affinity. Compounds with inhibitory effects on EED, a subunit of PRC2, can disrupt the protein-to-protein interaction between EED and EZH2, culminating in damaged PRC2 functions, H3K27me3-induced silencing of PRC2 expressions, and blockade of the triple-methylation of H3K27. Studies have shown that the PRC2 complex's component proteins and EZH2's histone (MTase HMTase) activities are highly dependent on the scaffold and modulating effects of EED. However, the secondary mutation of EZH2 may lead to acquired drug resistances, while the homologous EZH1 also has methyltransferase (MTase) activity that could limit the effects of EZH2 inhibitors. Ruihua Xu, President and Director of Sun Yat-Sen University Cancer Center, and President of the Chinese Society of Clinical Oncology, will be the principal investigator of this study.ĮZH2, which is highly expressed in multiple tumors in humans, was found to promote the development and progression of tumors, and targeted inhibition of EZH2's methyltransferase activity has already proved to be an effective mechanistic approach for cancer treatment. This multicenter, open-label Phase I dose-escalation and dose-expansion study is designed to assess the safety, pharmacokinetics, and efficacy of orally administered APG-5918 in patients with advanced solid tumors or hematologic malignancies.
Ascentage Pharma Logo (PRNewsfoto/Ascentage Pharma)
0 kommentar(er)
