Ascentage Pharma's EED inhibitor APG-5918 has been approved for Phase I clinical trial in China and will advance the clinical development of advanced solid tumors or hematologic malignancies

Ascentage Pharma (6855.
HK) announced on November 10 that APG-5918, a class 1 embryonic ectoderm development protein (EED) inhibitor under development, has been approved by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) to carry out phase I clinical trials
for the treatment of advanced solid tumors or hematologic malignancies.
Prior to this, the investigational variety has been approved in the United States for clinical trials for advanced solid tumors or hematological tumor indications, which is another major achievement of the company's "Sino-US dual report" strategy, basically realizing the simultaneous advancement
of China and the United States.
APG-5918 is the first Chinese original EED inhibitor
to enter the clinical stage.

This is a multicenter, open-label Phase I dose-escalation and dose-expansion clinical trial designed to evaluate the safety, pharmacokinetics, and efficacy
of oral administration of APG-5918 in patients with advanced solid tumors or hematologic malignancies.
Professor Xu Ruihua, President of the Chinese Society of Clinical Oncology, Director and Dean of the Cancer Center of Sun Yat-sen University, will serve as the principal investigator (PI)
of the clinical trial.

EZH2 is highly expressed in a variety of human cancers and promotes cancer occurrence and malignancy, and targeted methyltransferase activity to inhibit EZH2 has proven to be a successful cancer treatment strategy
.
Nevertheless, secondary mutations of EZH2 can produce acquired resistance, and its homologous EZH1 also has methyltransferase activity, both of which lead to limited
activity of EZH2 inhibitors.
It was found that the polyproteal and EZH2 activity of the PRC2 complex are highly dependent on the scaffold and regulatory effects of EED
.
Compounds that inhibit the PRC2 subunit EED can disrupt the protein-protein interaction (PPI) of EED-EZH2 and subsequently impair the function of PRC2, resulting in loss of PRC2 activity excited by H3K27me3 and preventing trimethylation of H3K27^[1].

Therefore, targeting EED protein has gained great attention
in recent years as an alternative inactivation strategy to inhibit PRC2.

APG-5918 is a novel potent and highly selective EED protein small molecule inhibitor with oral activity, which has a high binding affinity and has broad clinical application prospects
in hematological tumors, solid tumors and non-tumor indications by regulating tumor tissue epigenetics and tumor microenvironment.
APG-5918 selectively binds to the H3K27me3 domain on the EED protein, resulting in conformational changes in the EED H3K27me3 binding pocket, preventing the interaction
of EED with the histone methyltransferase EZH2.
Preliminary data demonstrate APG-5918's in vitro anti-tumor cell proliferation viability in multiple tumor cell lines, as well as antitumor activity
in the PDX/CDX model of EZH2-mutated B-cell non-Hodgkin lymphoma, INI1-negative malignant rhabdomyomas, BAP1-mutated mesothelioma, and prostate cancer.

Professor Xu Ruihua said: "Targeting the PRC2 complex protein, especially EED, may be effective in
tumors with certain genetic characteristics.
The EED inhibitor APG-5918 has shown clear target binding and target-related antitumor activity
in both in vitro and in vivo tests.
Further clinical studies are warranted to explore its efficacy
.
"

Dr.
Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "This is another major development following the approval of the clinical trial application for APG-5918 oncology indications in the United States, and it is also a reflection
of Ascentage's adherence to the Sino-US dual reporting strategy and global innovation strength.
We look forward to working with Dr.
Xu to actively advance the clinical development of APG-5918 and benefit more patients as soon as possible
.
" "

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       Reference

1.
Erokhin M, Chetverina O, Gy?rffy B, Tatarskiy V V, Mogila V, Shtil AA, et al.
Clinical correlations of polycomb repressive complex 2 in different tumor types.
Cancers 2021; 13:3155.