Yasheng Pharmaceutical announced on its wechat public account on November 10 (today) that the company is in the process of developing an original Class 1 new embryonic Ectodermal development protein (EED) inhibitor APG-5918, which has been approved by the National Medical Products Administration (NMPA) Drug Evaluation Center (CDE) for clinical trials. Phase I clinical trials will be conducted for the treatment of advanced solid tumors or hematological malignancies.
Prior to this, this strain in development has been approved to carry out clinical trials in the United States for the indications of advanced solid tumors or hematologic tumors, which is another major achievement of the company's "Sino-US double report" strategy, basically realizing the synchronous progress between China and the United States. APG-5918 is the first EED inhibitor to enter the clinical stage in China.
This is a multicenter, open phase I dose-escalation and dose-extension trial to evaluate the safety, pharmacokinetics and efficacy of oral APG-5918 in patients with advanced solid tumors or hematologic malignancies. Professor Xu Ruihua, President of the Chinese Society of Clinical Oncology and Director and President of the Cancer Prevention Center of Sun Yat-sen University, will be the principal investigator (PI) of the clinical trial.
EZH2 is highly expressed in a variety of human cancers and promotes carcinogenesis and malignancy, and targeting the inhibition of EZH2 methyltransferase activity has been shown to be a successful cancer treatment strategy. Nevertheless, secondary mutations in EZH2 can produce acquired resistance, and its homology, EZH1, also has methyltransferase activity, leading to limited EZH2 inhibitor activity. It was found that the polyproteinicity of PRC2 complex and EZH2 activity were highly dependent on the scaffold and regulatory role of EED. Compounds that inhibit PRC2 subunit EED disrupt protein-protein interactions (PPI) of ee-EZH2 and subsequently impair PRC2 function, resulting in loss of PRC2 activity stimulated by H3K27me3 and preventing trimethylation of H3K27 [1]. Therefore, targeting EED protein as an alternative inactivation strategy to inhibit PRC2 has gained great attention in recent years.
APG-5918 is a novel, powerful and highly selective EED protein small molecule inhibitor that is being developed by Yasheng Pharmaceutical with oral activity. With high binding affinity, APG-5918 has broad clinical application prospects in hematologic tumors, solid tumors and non-tumor indications by regulating tumor tissue epigenetics and tumor microenvironment. APG-5918 can selectively bind to the H3K27me3 domain on EED protein, resulting in a conformational change in EED H3K27me3 binding pocket, which prevents EED from interacting with histone methyltransferase EZH2. Preliminary data demonstrate the in vitro anti-tumor cell proliferative activity of APG-5918 in multiple tumor cell lines, as well as in PDX/CDX models of EZH2-mutated B-cell non-Hodgkin's lymphoma, INI1-negative malignant rhabdomioma, BAP1-mutated meselioma, and prostate cancer.
Professor Xu Ruihua, Director and Dean of the Cancer Prevention Center of Sun Yat-sen University, said:
Targeting PRC2 complex proteins, especially EED, may be effective in tumors with certain genetic characteristics. EED inhibitor APG-5918 demonstrated clear target-binding and target-related antitumor activity both in vitro and in vivo. It is worth further clinical research to explore its efficacy. Targeting PRC2 complex proteins, especially EED, may be effective in tumors with certain genetic characteristics. EED inhibitor APG-5918 demonstrated clear target-binding and target-related antitumor activity both in vitro and in vivo. It is worth further clinical research to explore its efficacy.
Dr. Zhai Yifan, Chief Medical Officer of ASeng Medicine, said:
This is another great progress after the clinical trial application for the tumor indication of APG-5918 was approved in the United States, and also reflects Axen's adherence to the Sino-US dual return strategy and global innovation strength. We look forward to cooperating with President Xu to actively promote the clinical development of APG-5918, so as to benefit more patients at an early date.
