Recent research has explored the antitumor potential of APG-5918, a novel small molecule that inhibits EED, a core component of the PRC2 complex responsible for histone methyltransferase activity. Dysregulation of PRC2 is frequently observed in prostate cancer (PCa) and is associated with poor prognosis, making EED an attractive therapeutic target.

Preclinical studies demonstrated that APG-5918 effectively inhibited the proliferation of prostate cancer cells in vitro, outperforming two EZH2 inhibitors and another EED inhibitor across multiple cell lines, including LNCaP (AR-dependent) and 22Rv1 (AR-independent, castration-resistant). APG-5918 showed potent IC50 values, indicating strong antiproliferative activity.

Importantly, combining APG-5918 with the AR antagonist enzalutamide resulted in a synergistic suppression of cancer cell growth. Mechanistically, APG-5918 induced dose-dependent cell cycle arrest at the G0/G1 phase, which was even more pronounced when used alongside enzalutamide.

In vivo studies reinforced these findings: in castrated mice bearing LNCaP tumors, APG-5918 alone showed substantial tumor growth inhibition (T/C = 40.78%), whereas enzalutamide alone had limited effects. Similarly, in 22Rv1 tumor-bearing mice, APG-5918 achieved superior antitumor activity at multiple doses, while enzalutamide remained largely ineffective. Importantly, treatment with APG-5918 was well tolerated, with no significant impact on body weight.

Pharmacodynamic analyses revealed that APG-5918 suppressed multiple key proteins involved in cancer progression, including H3K27me3, EED, EZH2, SUZ12, AR pathway components, ERG, DNA methylation factors (UHRF1, DNMT1), and anti-apoptotic regulators like MCL-1. It also downregulated important cell cycle proteins such as pRb, CDK4, and cyclin D1, with combination therapy enhancing these effects.

Overall, the study highlights APG-5918 as a promising therapeutic candidate for prostate cancer, either as monotherapy or in combination with AR-targeted treatments like enzalutamide. By targeting EED, APG-5918 offers a novel approach to combat both AR-dependent and resistant forms of the disease.

Based on these encouraging preclinical results, APG-5918 has entered clinical evaluation. A phase 1 clinical trial is currently underway to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of APG-5918 in patients with advanced solid tumors, including prostate cancer.

Source.

Clinical trial.