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Insight into the Inhibitory Mechanism of Embryonic Ectoderm Development Subunit by Triazolopyrimidine Derivatives as
Jianan Ju1, Hao Zhang1, Shanshan Guan2,3
1Institute of Theoretical Chemistry, College of Chemistry, Jilin University, 2 Liutiao Road, Changchun 130023, China.
Abstract:
Inhibition of the Embryonic Ectoderm Development (EED) subunit in Polycomb Repressive Complex 2 (PRC2) can inhibit tumor growth. In this paper, we selected six experimentally designed EED competitive Inhibitors of the triazolopyrimidine derivatives class. We investigated the difference in the binding mode of the natural substrate to the Inhibitors and the effects of differences in the parent nuclei, heads, and tails of the Inhibitors on the inhibitory capacity. The results showed that the binding free energy of this class of Inhibitors was close to or lower compared to the natural substrate, providing an energetic basis for competitive inhibition. For the Inhibitors, the presence of a strong negatively charged group at the 6-position of the parent nucleus or the 8'-position of the head would make the hydrogen atom on the head imino group prone to flip, resulting in the vertical movement of the parent nucleus, which significantly decreased the inhibitory ability. When the 6-position of the parent nucleus was a nonpolar group, the parent nucleus would move horizontally, slightly decreasing the inhibitory ability. When the 8'-position of the head was methylene, it formed an intramolecular hydrophobic interaction with the benzene ring on the tail, resulting in a significant increase in inhibition ability.
Insights
Targeting the Embryonic Ectoderm Development (EED) subunit of Polycomb Repressive Complex 2 (PRC2) inhibits tumor growth. Triazolopyrimidine derivatives show potent EED inhibition, with structural modifications enhancing their efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Polycomb Repressive Complex 2 (PRC2) plays a crucial role in epigenetic regulation.
- Inhibition of the Embryonic Ectoderm Development (EED) subunit of PRC2 is a promising strategy for cancer therapy.
- Understanding the structure-activity relationships of EED inhibitors is vital for drug development.
Purpose of the Study:
- To investigate the binding modes of triazolopyrimidine-based EED inhibitors.
- To evaluate the impact of structural variations (parent nucleus, head, and tail) on inhibitory capacity.
- To establish an energetic basis for competitive inhibition by these compounds.
Main Methods:
- Computational modeling to analyze binding modes and free energy.
- Synthesis and experimental design of six EED competitive inhibitors.
- Structure-activity relationship (SAR) analysis of triazolopyrimidine derivatives.
Main Results:
- The binding free energy of the inhibitors was comparable to or lower than the natural substrate.
- Specific substitutions on the parent nucleus and head significantly influenced inhibitory activity.
- Intramolecular hydrophobic interactions were identified as key to enhanced inhibition.
Conclusions:
- Triazolopyrimidine derivatives are effective competitive inhibitors of EED.
- Strategic modifications can optimize the inhibitory potential of these compounds.
- The study provides valuable insights for designing novel anticancer agents targeting PRC2.
