Polycomb protein EED is a member of the Polycomb-group (PcG) family. Specifically, the Polycomb group (PCG) is a class of proteins responsible for cell differentiation during development through transcriptional inhibition. In mammals, PcG protein is part of two major transcriptional inhibition complexes, known as PRC1 and PRC2. Besides, the core PRC2 complex consists of three proteins: catalytic subunits EZH2, EED, and SUZ12. Moreover, as an epigenetic transcription regulator, PRC2 plays an important role in many biological processes such as stem cell maintenance and DNA repair. By directly binding to H3K27me3, EED located the PRC2 complex on chromatin substrate and activated methyltransferase activity. Because the imbalance of PRC2 activity is relevant to various forms of human cancer, it is necessary to develop small molecule inhibitors targeting PRC2 activity. EEDi-5285 is a potent and orally active embryonic ectoderm development (EED) inhibitor.
EEDi-5285 is a potent and orally active embryonic ectoderm development (EED) inhibitor.
But, how does EEDi-5285 protect against cancer cells via EED? Let’s discuss it in detail. First of all, EEDi-5285 is a potent and orally active EED inhibitor with an IC50 value of 0.2 nM for binds to the EED protein. Furthermore, EEDi-5285 has anti-cancer activity.
In the second place, EEDi-5285 (compound 28) inhibits cell growth with IC50 values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively. Meanwhile, EEDi-5285 with 50-100 mg/kg/day by oral gavage achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice for 28 days. Nonetheless, a single 100 mg/kg oral administration of EEDi-5285 effectively reduces the level of H3K27me3 at 24 h in KARPAS422 tumor tissue in mice. Importantly, EEDi-5285 achieves a Cmax of 1.8 μM and an AUC of 6.0 h▪μg/ml with 10 mg/kg oral administration. Particularly, EEDi-5285 has a moderate volume of distribution of 1.4 L/kg and a terminal T1/2 of approximately 2 h.
All in all, EEDi-5285 is a potent and orally active embryonic ectoderm development (EED) inhibitor.
References:
Rohan Kalyan Rej, et al. J Med Chem. 2020 Jul 9;63(13):7252-7267.