Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Jul 2

PMID 34203106

Citations 32

Authors

Gabriel LaPlante

Wei Zhang

Affiliations

Soon will be listed here.

Abstract

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

Citing Articles

A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins.

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Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions.

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The Role of Ubiquitination in Osteosarcoma Development and Therapies.

Mao P, Feng Z, Liu Y, Zhang K, Zhao G, Lei Z Biomolecules. 2024; 14(7).

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Nano-Proteolysis Targeting Chimeras (Nano-PROTACs) in Cancer Therapy.

Song Y, Dong Q, Ni Y, Xu X, Chen C, Chen W Int J Nanomedicine. 2024; 19:5739-5761.

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