Issue 4, 2021

Targeting protein–protein interactions in the DNA damage response pathways for cancer chemotherapy

Abstract

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alteration is a hallmark of cancer, with the deficiency in one DDR capability often compensated by a dependency on alternative pathways endowing cancer cells with survival and growth advantage. Targeting these DDR pathways has provided multiple opportunities for the development of cancer therapies. Traditional drug discovery has mainly focused on catalytic inhibitors that block enzyme active sites, which limits the number of potential drug targets within the DDR pathways. This review article describes the emerging approach to the development of cancer therapeutics targeting essential protein–protein interactions (PPIs) in the DDR network. The overall strategy for the structure-based design of small molecule PPI inhibitors is discussed, followed by an overview of the major DNA damage sensing, DNA repair, and DNA damage tolerance pathways with a specific focus on PPI targets for anti-cancer drug design. The existing small molecule inhibitors of DDR PPIs are summarized that selectively kill cancer cells and/or sensitize cancers to front-line genotoxic therapies, and a range of new PPI targets are proposed that may lead to the development of novel chemotherapeutics.

Graphical abstract: Targeting protein–protein interactions in the DNA damage response pathways for cancer chemotherapy

Article information

Article type
Review Article
Submitted
02 maj 2021
Accepted
20 jun 2021
First published
21 jun 2021
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2021,2, 1167-1195

Targeting protein–protein interactions in the DNA damage response pathways for cancer chemotherapy

K. S. McPherson and D. M. Korzhnev, RSC Chem. Biol., 2021, 2, 1167 DOI: 10.1039/D1CB00101A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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