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.

Advantages of allostery 

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.

An overview of proteome complexity. Figure source: Nature. 2016 September 15; 537(7620): 328–338. 

Finding allosteric sites

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 structure based data, promoted by HotSpot TherapeuticsNimbus Therapeutics and Relay Therapeutics, the latter using “motion based hypotheses”, described in the Biocentury article.

To overcome challenges of allosteric drug discovery, at HotSpot we are integrating rational structure-based approaches, proprietary chemistry, and tailored assay formats.

  • Structure-based approaches: Our SpotFinder™ platform identifies regulatory pockets on proteins that can be targeted with small molecules.  We leverage large quantities of structural and sequence information to identify common allosteric pockets within and across target classes, thereby creating annotated ‘pocketomes’ which function like encyclopedias of the identified pockets.  Using cutting edge machine learning approaches, we are uncovering the unique fingerprint of allosteric regulatory pockets.
  • Proprietary chemistry: We invest heavily in custom chemistry to drug the identified sites in order to go beyond the active site chemotypes that are typically poorly suited for allosteric sites.  This philosophy is borne out by our colleagues at Vividion Therapeutics who are demonstrating the value of exploring new covalent chemical space in the context of a powerful proteomics platform. Furthermore, like Revolution Medicines, we exclusively focus on targets that are structure enabled, as this rational approach allows us to progress the chemistry more rapidly. 
  • Tailored assay formats: It is critical to rapidly confirm the predictions of the platform through carefully engineered proteins and cell-based methods. This way, we ensure that our molecules are hunting their targets “in the wild” and not only just in silico.

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.

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