SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding
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Cited by (26)
Chemical inhibitors targeting histone methylation readers
2024, Pharmacology and TherapeuticsRecent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs
2022, European Journal of Medicinal ChemistryCitation Excerpt :Further chemical optimization by changing the 2-methylpyridine of 40 to 1-methylpyrazole provided compound 41 with a three-fold boost in EED binding potency (Kd = 0.9 μM) and enhanced cellular activity (IC50 = 2.1 μM) (Fig. 15). Researchers from AbbVie Inc. identified compound 42 (EED709) as a modestly potent EED inhibitor (Ki = 600 nM) through a high-throughput TSA-based screen against EED protein (Fig. 16A) [99]. As shown in Fig. 16B, the co-crystal structure of EED709 in complex with EED revealed that compound EED709 occupied the H3K27me3 binding pocket, which was obviously remodeled to accommodate the pyrrolidine ligand.
Exploiting binding-site arginines in drug design: Recent examples
2020, Bioorganic and Medicinal Chemistry LettersA drug repurposing screening reveals a novel epigenetic activity of hydroxychloroquine
2019, European Journal of Medicinal ChemistryCitation Excerpt :In particular, we correlated the Ki (nM) and the G-Score (kcal/mol) of each ligand, obtaining the best results for the 5K0M PDB structure (for details see Table S1 of the Supplementary Material). In order to define the best 3D structure for performing VS calculations, the active compounds extracted from the previously selected PDB models [27] and characterized by a dimethylamino pyrrolidine scaffold, together with A395N [26], a structural analog, were used for the R2 calculation of the EED selected PDB models (for 2D structure details see Fig. S1 of the Supplementary Material). Thus, the ligands were adjusted considering the ionization state at physiological 7.4 pH and, afterwards, energy minimized by OPLS_2005 force field [45], implemented in the LigPrep platform ver.
Polycomb repressive complex 2 inhibitors: emerging epigenetic modulators
2019, Drug Discovery TodayCitation Excerpt :Moreover, this compound also stabilizes the complex key interactions such as H-bonds from the dimethylamine to a highly coordinated water, as well as hydrophobic and van der Waals interactions with catalytic amino acids in the active site. A SAR study by Curtin et al. [56] on this compound demonstrated that modification of the indole and benzyl moieties substantially improved binding and cellular activities. The SAR work began with a thorough survey of N-benzyl substituents and revealed a strong preference for 2,6-disubstitution.
Epigenetic small molecule modulators of histone and DNA methylation
2018, Current Opinion in Chemical BiologyCitation Excerpt :Catalytic stimulation of EZH2 is ultimately achieved upon binding of the H3K27me3 mark to EED [143••]. Inhibitors which disrupt the binding of the H3K27me3 peptide to EED were developed as an alternative strategy to inhibit enzymatic EZH2 activity at the active site [144,145••,146••,147,148••]. A-395 and EED226 (Figure 4) were shown to strongly inhibit the binding of H3K27me3 to EED (Kd 1.5 nm and 22 nm; respectively), inhibit PRC2 activity (IC50 18 nm and 23 nm; respectively), and induce regression of cancer cells in vivo [144,148••].
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