I was excited to participate in Allison Johnson’s recent Biocentury article reflecting on the growing interest of industry in allostery and why it’s back in fashion. I wanted to comment on some areas that resonate strongly for me.
The advantages of allosteric molecules are well characterized: allosteric drugs encounter less competition from endogenous substrates when targeting proteins leading to enhanced potency in living systems; and due to their highly selective nature, allosteric molecules often have an improved therapeutic index. However, when taking a slightly closer look, it becomes apparent that the actual “magic” of allostery lies within Nature’s myriad ways of controlling protein function (see figure below). Utilizing modes of action, allostery allows one to imagine drug molecules with a broader set of pharmacological properties than traditional active site modulators. Whilst active site drugs simply shut down substrate turnover, an allosteric modulator can change a protein’s shape and additionally prevent its localization to a different part of the cell. These traits of allostery provide a new canvass for creating important therapeutic molecules and open up new pathways within the area of highly differentiated pharmacology.
Despite the promise of allostery, the identification of allosteric binding sites and respective binding partners remains challenging. Therefore, it is exciting that HotSpot Therapeutics is joined by others who are seeking to break open this area of science.
It is well recognized that many allosteric inhibitors are found through phenotypic screening but, even if you are successful in identifying a well-behaved ligand, it is far from guaranteed that you can work out the actual underlying mechanism.
More rational approaches take advantage of
To overcome challenges of allosteric drug discovery, at HotSpot we are integrating rational structure-based approaches, proprietary chemistry, and tailored assay formats.
This combined approach has allowed us to create a platform that is now delivering chemical starting points across a number of sought-after target classes. As shown by the diverse landscape of allosteric companies described in the Biocentury article, it is really an exciting time to be pushing the boundaries of what is possible with chemistry. In the end, patients are going to benefit from the breadth of targets and diseases that we are going to be able to address.