Mark Mitchell

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Developing Novel covalent PHOSTACs for Targeted Dephosphorylation

There is currently an unmet need for the development of new therapeutics that sufficiently cover cancers driven by KRAS mutations. These mutations lead to the overactivation of the ERK1/2 MAPK pathway, which plays an important role in cell growth and proliferation, resulting in tumour development. An important part of the pathway is the RAF-MEK-ERK kinase cascade, with each component having on/off signalling functions dictated by phosphorylation/ dephosphorylation events, respectively. Phosphorylation is governed by kinases whilst dephosphorylation is facilitated by phosphatases. Current therapeutics are aimed at inhibiting the kinases responsible for activating signalling however, these treatments have been limited by added toxicity due to off-target effects and development of inhibitor resistance mechanisms. We are investigating a new branch of therapeutics that can increase the deactivation of this signalling cascade by recruiting a suitable phosphatase and bringing it into proximity with our protein of interest (POI), enabling accelerated targeted dephosphorylation that will restore the signalling pathway to more normal levels and inhibit tumour growth. These technologies are called PHOSphorlyating Targeteing Chimeras (PHOSTACs) and consist of three parts: (1) small molecule binder of the phosphatase – we will develop novel covalent ligands for our phosphatase of interest. (2) small molecule binder of the POI - we will use different inhibitors from the literature. (3) a small linker that connects the two molecules, enabling proximity-induced pharmacology – we will employ linkers of different sizes and length and make a library of PHOSTACs for testing in vitro and in cells.

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