Seminar: Next-generation precision medicine through covalent reactivity — From click chemistry to ‘undruggable’ targets

Covalent chemical reactivity is a powerful means for the discovery of diverse functional molecules. In this talk, I will first focus on the next-generation click chemistry, sulfur fluoride exchange (SuFEx). I will demonstrate how the selectivity, efficiency and fidelity of modular SuFEx reactions accelerate the discovery of therapeutic and diagnostic molecules. I will then highlight the recent development of in vivo active covalent inhibitors targeting K-Ras(G12D), the most common activating mutation found in human cancer. K-Ras lacks surface topology for reversible small molecule binding, leading to its notorious characterization as ‘undruggable’. I will report on a series of compounds that rely on covalent reaction with mutant aspartic acid for binding and therefore do not affect the wildtype protein. I will discuss the potency and selectivity of the covalent K-Ras(G12D) inhibitors both in vitro and in vivo.