China-based Jing Medicine Technology (Shanghai) Co., Ltd’s HJM-353 has obtained clinical trial approvals in the US and China. The investigational embryonic ectoderm development (EED) inhibitor is expected to enter a Phase I clinical study for advanced blood cancer and solid tumors.
Mechanism of Action and Development
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase complex composed of three core subunits: EZH2 (or EZH1), EED, and SUZ12. Studies have shown that PRC2 dysregulation is associated with the occurrence, progression, and poor prognosis of hematopoietic malignancies and solid tumors. EZH2 is overexpressed or has gain-of-function mutations in a variety of cancers. However, although the role of EZH2 inhibitors in cancer treatment has been clinically verified, acquired drug resistance caused by secondary mutations of EZH2 limits their clinical application. EED can allosterically regulate the activity of EZH2 and stabilize the structure of the PRC2 complex, meaning that EED inhibitors are unaffected by EZH2 drug-resistant mutations while inhibiting EZH1 activity.
Preclinical Data and Future Prospects
Under co-development by Jing Medicine and ShanghaiTech University, HJM-353 is a novel, potent, and highly selective EED inhibitor with oral activity. The molecule blocks trimethylation of histone H3 lysine 27 (H3K27me3), binds to EED, and disrupts the H3K27me3-EED-EZH2 interaction, thereby inhibiting the enzymatic activity of PRC2. Preclinical pharmacokinetic tests have been positive, with good bioavailability in many species of animals and a large safety window, alongside anti-tumor activity in a variety of cell and animal models, including strains resistant to tazemetostat.-Fineline Info & Tech
