Small molecule-mediated protein knockdown as a new approach to drug discovery. Issue 12 (4th August 2016)

• Record Type: Journal Article
• Authors: Tinworth, Christopher P.; Lithgow, Hannah; Churcher, Ian
• Is Part Of: MedChemComm. Volume 7:Issue 12(2016:Dec.)
• Page Start: 2206
• Page End: 2216
• Publication Date: 2016-08-04
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c6md00347h
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : Research into degradation of cellular proteins induced by small molecule agents known as Protacs has gathered pace recently. This article reviews recent progress and assesses the challenges to be addressed to enable clinical evaluation of agents. Abstract : The concept of using peptidic bifunctional molecules to allow recruitment of ubiquitin E3 ligases to induce the degradation of specific intracellular proteins was first demonstrated in 2001 but, following the extension of this approach to non-peptidic agents, its utility has been greatly expanded. As the number of E3 ligases amenable to recruitment also continues to grow, induced protein degradation now represents a new pharmacological strategy for highly efficient chemical protein knockdown with utility both as a chemical biology tool and also potentially as a clinically-useful therapeutic modality. We survey some of the recent advances in the design of small molecule chemical inducers of protein degradation and the potential challenges that will need to be overcome in order to allow clinical evaluation.