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Redefining Druggability Using Chemoproteomic Platforms

Abstract

The Undruggable Proteome – those proteins which do not have a canonical small molecule binding pocket – poses one of the largest problems in modern drug discovery. The genomics revolution linked the function of thousands of proteins to corresponding diseases, but many of these disease-causing proteins are difficult or seemingly impossible to target or study with traditional small-molecule based approaches. Recently, chemoproteomics – the combination of chemical-biology methods with proteomics – has given us new tools to approach this undruggable proteome, especially in combination with covalently-acting probes or ligands. Using these emerging technologies this work shows three examples of how chemoproteomics can enable both tool development for better understanding of undruggable proteins and also allow direct engagement with such proteins for drug development.

Firstly, we show that NHS-esters are viable chemoproteomic probes, allowing the profiling of the reactivity of thousands of lysines in complex proteomes. Furthermore, scaffolds bearing an NHS-ester have surprising specificity, opening the door for covalent ligand discovery around the NHS-ester warhead. Secondly, we further highlight the efficacy of covalent molecules in targeting undruggable proteins by mapping the anti-cancer targets of Withaferin A, a natural product, with chemoproteomic methods. We show the primary target is a traditionally undruggable site on a traditionally undruggable protein, cysteine 377 on the scaffolding subunit of the phosphatase PP2A (PPP2R1A). We are then able to screen simple covalent fragments against this target, to find a small, synthetically-accessible fragment which binds same site and recapitulates the biochemical activity of Withaferin A. Lastly, we leverage similar covalent fragment screening approaches to discover a non-functional ligand against the E3 ligase RNF4. We use this ligand with success in targeted protein degradation applications, demonstrating the synergy between chemoproteomics and other emerging approaches to tackle to undruggable proteome.

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