Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads

There is growing interest in covalent targeted inhibitors
in drug
discovery against previously “undruggable” sites and
targets. These molecules typically feature an electrophilic warhead
that reacts with nucleophilic groups of protein residues, most notably
the thiol group of cysteines. One main challenge in the field is to
develop versatile utilizable warheads. Here, we characterize the unique
features of novel arsenous warheads for reaction with thiol species
in a reversible manner and further demonstrate that organoarsenic
probes can be chemically tuned toward specific molecular targets by
developing selective and potent inhibitors of pyruvate kinase M2 (PKM2).
We show that compound 24 is a covalent and allosteric
inhibitor of PKM2 and its orally bioavailable prodrug 25 exerts efficacious inhibition of PKM2-dependent tumor growth in vitro and in vivo. Our results introduce 25 and its derivatives as useful pharmacological tools and
provide a general road map for targeting the protein cysteinome using
arsenous warheads.