# De Novo-Designed APC/C Inhibitors Provide a Rationale for Targeting RING-Type E3 Ubiquitin Ligases

## TL;DR

Scientists designed new inhibitors for a type of enzyme involved in disease, showing they can be targeted effectively.

## Contribution

A pharmacophore-based strategy for designing RING domain inhibitors, validated with APC/C inhibition.

## Key findings

- Designed peptidomimetics that bind and inhibit APC/C RING domains in vitro.
- Optimized molecules show chemical stability, permeability, and specificity for APC/C inhibition in cancer cells.
- Results support targeting RING-type E3 ubiquitin ligases as a viable therapeutic strategy.

## Abstract

The ubiquitin system
represents an attractive pharmacological target
for numerous pathological processes, including cancer and neurodegeneration.
RING domain-containing E3 ubiquitin ligases constitute the largest
class of ubiquitin enzymes, providing a scaffold for substrate recognition
and catalysis. Their shallow groove recognition interfaces involving
discontinuous epitopes and a lack of defined binding pockets have
largely rendered them undruggable. Inspired by natural RING inhibitors,
we have developed a pharmacophore-based strategy for the rational
design of peptidomimetics targeting RING domains, and we demonstrate
its feasibility by using the macromolecular APC/C complex (anaphase-promoting
complex/cyclosome). We designed scaffolds binding to the APC/C RING
domain and efficiently inhibiting its activity in vitro. Iterative structure-based design and experimental studies to optimize
their chemical stability, permeability, and specificity lead to new
hydrocarbon-stapled-based molecules inhibiting APC/C in vitro and in cancer cells. Our results provide a robust rationale for
targeting RING-containing enzymes of therapeutic value and promising
leads for clinical APC/C inhibition.