Conventional therapeutics target the catalytic or active site and are effective in a fraction of known targets. Competition with enzyme substrates minimizes active site inhibitor effectiveness while cross-reactivity against other proteins leads to side effects. Additionally, pharmaceutical properties can be suboptimal due to the topography of these sites.

In contrast, evolution has crafted control mechanisms with selectivity and specificity. At the heart of these regulatory regions are privileged allosteric sites called natural hotspots that offer attractive biological real estate for drug discovery.

Hotspot medicines offer

The ability to target previously inaccessible biological pathways relevant to serious diseases.

Exquisite selectivity and specificity. Unlike active sites, natural hotspots are structurally unique.

Powerful, differentiated pharmacology. Hotspot inhibitors do not compete with substrate and, in the context of the cell, can disrupt protein complexes and impact protein stability.

Attractive drug-like characteristics. Natural hotspots allow chemists to exploit a range of new molecular scaffolds or chemotypes.

Hotspots in action

Learn more
about natural
Traditional drug discovery aims to shut down a protein's catalytic site.

Problems with catalytic site:

Competition with natural substrate
Reduced potency
Similar across proteins
Hydrophobic, charged site
Poor drug-like properties

Introducing natural hotspots

Nature uses natural hotspots to control proteins precisely.
A flexible protein 'tail' ...
... is chemically modified by nature.
The tail then moves ...
... to interact with the natural hotspot ...
... controlling protein activity like a molecular 'gearbox'.
At HotSpot, we are creating medicines that target natural hotspots ...
... interfering with the function of the protein.

Targeting natural hotspots
has many advantages:

No competition with substrate
Highly potent
Unique site, highly selective
Attractive safety profile
Balanced charge & lipophilicity
Low dose, oral

Through natural hotspots, evolution has devised a means to selectively correct for chemical imbalances and dysregulation to restore health and proper functioning. We see this in both normal biological activity and in disease. In select cases, natural hotspots have been successfully targeted to create important new medicines including those directed at Acetyl CoA Carboxylase (AAC), Bcr-abl and HIF-2a.

HotSpot has designed the first and only technology platform, Smart Allosteryâ„¢, to systematically identify and drug natural hotspots across the proteome, including protein classes largely considered undruggable.