# Identification of Novel β‐Lactam Derivatives as Proteasome Inhibitors for Antitumor Therapy

## TL;DR

Researchers designed and tested new β-lactam-based proteasome inhibitors, finding one compound that effectively stops cancer cell growth by blocking proteasome activity.

## Contribution

The paper introduces novel β-lactam derivatives as effective proteasome inhibitors with antitumor potential.

## Key findings

- Compound 66 showed micromolar-range proteasome inhibitory activity.
- Compound 66 induced apoptosis in RS4;11 cells by inhibiting proteasome pathways.
- Compound 66 had antiproliferative effects with IC50 values below 1 μM against RS4;11 cells.

## Abstract

A series of dipeptidic proteasome inhibitors with β‐lactam as the C‐terminus was designed and synthesized. Biochemical evaluations of their effects on chymotrypsin‐like (CT‐L) activity revealed that some of them had inhibitory activity against the proteasome, with IC50 values in the micromolar range. Based on the enzymatic results, structure–activity relationships (SAR) were discussed in detail. Some potent compounds were further selected for antiproliferative assays toward multiple cancer cell lines, with compounds 66 and 78 demonstrating activity against RS4;11 cells and IC50 values of less than 1 μM. Additionally, cellular mechanistic studies indicated that these effects were linked to their ability to inhibit proteasome signal pathways and to induce apoptosis in RS4;11 cells, as demonstrated by flow cytometry. Collectively, these results illustrate that compound 66 is a potent proteasome inhibitor with significant potential as an antitumor agent.

A series of dipeptidic proteasome inhibitors with β‐lactam as the C‐terminus was designed and synthesized. Compound 66 exhibited excellent proteasome inhibitory activities and displayed potent antiproliferative activities against RS4;11 cells.