Bisthioether Stapled Peptides Inhibit PRC2 Assembly
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Solution Overview
Problem
Current EZH2 inhibitors for treating cancer develop secondary mutants resistant to treatment due to extended dosing, necessitating the development of alternative inhibitors that target different domains of the Polycomb Repressive Complex 2 (PRC2) without competing with SAM for the catalytic SET domain.
Innovation Solution
Development of novel bisthioether stapled peptides that act as allosteric inhibitors of PRC2, targeting crucial protein interfaces such as the SANT1L-SBD interaction in EZH2, the SUZ12-VEFS domain interaction, and the Nurff55-SUZ12 interaction, disrupting the complex's assembly and histone methyltransferase activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current EZH2 inhibitors are used for extended dosing, then cancer treatment effectiveness is improved, but secondary EZH2 mutants resistant to treatment develop
Solution Approach 1:
Instead of inhibiting the catalytic SET domain of EZH2 directly (the conventional approach), the patent inverts the strategy by targeting allosteric sites on PRC2 complex subunits (EED, SUZ12, RbAp48). This indirect approach prevents direct selection pressure on EZH2 catalytic activity, thereby avoiding the development of EZH2 mutants that would be resistant to direct catalytic inhibition.
Solution Approach 2:
The patent introduces peptide inhibitors as intermediary molecules that bind to allosteric sites on PRC2 complex subunits rather than directly competing with SAM at the catalytic SET domain. These peptide intermediaries disrupt PRC2 complex assembly and function indirectly, preventing the direct evolutionary pressure that leads to resistant EZH2 mutants.
2Adaptability or versatility
If allosteric inhibitors targeting PRC2 protein interfaces are developed, then resistance profiles are overcome, but inhibitor design complexity increases
Solution Approach 1:
The patent segments the PRC2 complex into its individual subunits (EED, SUZ12, RbAp48) and develops separate peptide inhibitors targeting specific protein interfaces of each subunit. This segmentation allows for modular inhibitor design, where each peptide targets a specific interface (e.g., EZH2-SUZ12, EED-SUZ12), simplifying the design process compared to attempting to inhibit the entire complex simultaneously.
Solution Approach 2:
The patent applies local quality by designing peptides with specific sequences and modifications (e.g., N-terminal acetylation, C-terminal amide, stapling at specific positions) optimized for binding to particular local interfaces on PRC2 subunits. Each peptide's structure is locally optimized for its specific target interface, allowing precise disruption of individual protein-protein interactions within the complex.
Data Source
AI summary
This disclosure describes three novel bisthioether stapled peptides as allosteric inhibitors of Polycomb Repressive Complex 2 (PRC2) catalytic function with demonstrated cell permeability, potent activity in physiological conditions, and strong antiproliferative effects on cancer cells. These inhibitors target, for the first time, two protein interfaces in PRC2 that are crucial for its proper assembling and thus for its histone methyltransferase activity.