HY809382: PRC2 Degrader Which Works With EZH2 Inhibitors Resistant Prostate Cancer

Prostate cancer becomes especially hard to treat when it turns resistant to hormone therapies like enzalutamide, largely because of a protein complex called PRC2 that shuts down genes needed to fight tumors. PRC2’s key parts, EZH2 and EED, fuel cancer growth, immune evasion, and drug resistance in prostate tumors, as well as others like endometrial and lung cancers. While EZH2 inhibitors such as tazemetostat gained FDA approval for lymphomas and sarcomas, they often fall short in prostate cancer due to EZH2 mutations or EZH1 stepping in as a backup.

HY809382 changes that approach. This oral drug targets EED directly, triggering its degradation and dismantling the entire PRC2 complex, unlike inhibitors that just block one function. In lab dishes, it halted growth in prostate cancer cell lines more potently than the EZH2 inhibitor PF-06821497 or EED inhibitor APG-5918 under the same conditions. When given once daily by mouth to mice with human prostate tumors, HY809382 shrank them in a clear dose-response way, showing strong antitumor power.

Its real promise shines in tough cases. In castration-resistant prostate cancer models, HY809382 teamed up with enzalutamide for synergistic tumor suppression, potentially extending treatment benefits for advanced patients. Critically, it overcame clinically seen EZH2 mutations that sideline approved inhibitors, staying effective in both cells and mouse xenografts.

HY809382 remains preclinical with no listed human trials for prostate cancer, though related PRC2 drugs advance in combinations like with enzalutamide.

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