Targeting the undruggable proteome: the small molecules of my dreams

Abstract

Biologically active small molecules have long proven useful in the exploration of cell biology. Although many early compounds were by-products of drug development efforts, recent increased small molecule screening efforts in academia have expanded the repertoire of biological processes investigated to include areas of biology that are not of immediate pharmaceutical interest. Many of these new bioassays score for small molecule-induced phenotypic changes at the cellular or even organismal level and thus have been described as "chemical genetic" screens. However, this analogy with traditional genetic screens is misleading; although each gene has roughly an equivalent chance of being mutated in a traditional genetic screen, the amount of "proteomic space" that a chemical genetics approach can reach using current small molecule libraries is considerably smaller. Thus, new chemical biology methodologies are needed to target the remaining "undruggable proteome" with small druglike molecules.

Figure 1. Strategies for employing cellular protein degradation machinery to control intracellular protein levels

A) Schematic of Inducing Protein Degradation via Recruitment to the Proteasome or Lysosome. B) Design of a PROTAC-based Library Targeting Protein Function Independently of Protein Class