Bifunctional Apcin-A Compounds for Cdc20 Degradation in Cancer
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Solution Overview
Problem
Current anti-mitotic drugs targeting the Cdc20-APC/C pathway face challenges in effectively inhibiting mitosis and suppressing cancer cell growth in vivo, limiting their clinical translation.
Innovation Solution
Development of bifunctional compounds that recruit endogenous ubiquitin protein ligases to induce ubiquitinylation and degradation of Cdc20, utilizing moieties like Apcin-A and VHL E3 ubiquitin ligase to form a ternary complex for targeted protein destruction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-mitotic drugs targeting the Cdc20-APC/C pathway are used, then mitosis inhibition is achieved, but effectiveness in suppressing cancer cell growth in vivo is limited
Solution Approach 1:
The drug is divided into two distinct functional moieties: a Cdc20-binding moiety (e.g., Apcin-A) and an E3 ubiquitin ligase-binding moiety (e.g., VHL ligand). These segments are connected by a linker to form a bifunctional compound that can simultaneously bind both targets, thereby improving therapeutic effectiveness while maintaining manageable structural complexity through modular design
Solution Approach 2:
The bifunctional compound acts as an intermediary that bridges Cdc20 and E3 ubiquitin ligase, forming a ternary complex. This intermediary structure enables the recruitment of endogenous ubiquitin protein ligases to induce ubiquitinylation and degradation of Cdc20, thereby enhancing the drug's ability to suppress cancer cell growth in vivo
2Reliability
If bifunctional compounds are developed to recruit E3 ubiquitin ligases, then Cdc20 degradation is induced, but compound structure complexity increases
Solution Approach 1:
The bifunctional compound is designed to perform multiple functions within a single molecular structure: it binds to Cdc20, recruits E3 ubiquitin ligase, and facilitates ubiquitinylation. This multi-functionality achieves efficient Cdc20 degradation while consolidating what would otherwise require multiple separate molecules into one compound, thereby managing structural complexity
Solution Approach 2:
The compound combines different functional elements (Cdc20-binding moiety, linker, and E3 ligase-binding moiety) into a composite molecular structure. This composite design integrates the capabilities of different moieties to achieve synergistic effects in Cdc20 degradation while maintaining a unified compound structure
Data Source
AI summary
Described herein are compounds of Formula I, or their pharmaceutically acceptable salts thereof, compositions comprising the same, and methods of using such compounds or compositions in inducing Cdc20 degradation in a cell, blocking mitotic progression, inhibiting tumor proliferation, treating cancer, and/or re-sensitizing a subject to cancer treatment with tamoxifen.