Opening up a treasure trove of new drug target opportunities

By using novel boronic acid chemistry our scientists have generated covalent inhibitors of Mcl-1, a notoriously difficult and key target in oncology

For the first time, scientists from our Innovative Medicines & Early Development (IMED) Biotech Unit have shown that it is possible to inhibit high value protein-protein interaction (PPIs) drug targets, such as Mcl-1, through the use of novel lysine targeting covalent warheads.

Targeted covalent inhibition (TCI) has proven to be a successful approach in the design of a number of therapeutics and one used in the discovery of AstraZeneca’s EGFRm inhibitor, for the treatment of non-small cell lung cancer. In this case, a reactive cysteine was present in the binding pocket which could be targeted using an electrophilic warhead.  But, to date our chemists have been limited in the types of amino acid residues they can covalently modify with such approach.

Inspired by a piece of academic research, our oncology medicinal chemists and discovery scientists have designed and generated a series of novel TCIs containing boronic acid that targets lysine, a less reactive amino acid.

In the recent issue of Nature Chemistry Biology, the IMED team go on to show that it is possible to use a non-catalytic lysine residue in the PPI target, Mcl-1, to achieve covalent reversible inhibition. As lysine is an amino acid commonly found in binding sites across all relevant drug target classes, this is potentially game-changing as it could enable medicinal chemists to design covalent inhibitors for many proteins that would previously have been inaccessible to small molecule drugs.

“We have made tremendous progress, advancing our medicinal chemistry approaches to generate small molecules that can covalently modify non-catalytic lysine residues in PPI targets. This is not only important for discovery of potent Mcl-1 inhibitors but also opens up a broader opportunity to incorporate boronic acid warheads into TCIs to covalently inhibit a wider range of drug targets”, says Qibin Su, Oncology Medicinal Chemist, IMED Biotech Unit.


About PPIs:

Protein-protein interactions (PPIs) are characterised by the direct interaction between at least 2 proteins and have a critical role in regulating a wide range of different biological processes including signalling pathways linked to human disease. The human ‘interactome’ is thought to contain as many as 300K PPIs thus is a potentially rich source of novel drug targets. The binding interface between two interacting proteins is often complex and can cover a relatively large area on each protein.  Furthermore, the interaction is also typically characterised by ‘hotspot’ regions that disproportionately drive binding and can be dispersed across the binding interface. This adds to the challenge of finding small molecules that can successfully disrupt a PPI. Nevertheless, progress continues to be made in finding small molecule inhibitors of PPIs with several notable examples now in clinical development.