Conventional therapeutics target the catalytic function or active site of an enzyme and are effective in just a fraction of known disease targets. Competition with the enzyme’s substrate minimizes their effectiveness while cross-reactivity against other proteins in the body leads to unwanted side effects. Additionally, pharmaceutical properties can be suboptimal due to the topography of these sites.

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

Hotspot medicines offer

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

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

Powerful, differentiated in vivo 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. Hotspots allow chemists to exploit a range of new molecular scaffolds or chemotypes.

Hotspots in action

Learn more
about regulatory
hotspots
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
Non-selective
Hydrophobic, charged site
Poor drug-like properties

Introducing regulatory hotspots

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

Targeting regulatory hotspots
has many advantages:

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

Through regulatory hotspots, Nature 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 a select number of cases, regulatory hotspots have been successfully targeted to create important new medicines including with Acetyl CoA Carboxylase (AAC) and Bcr-abl.

HotSpot Therapeutics has designed the first and only technology platform, SpotFinder™, to identify and drug regulatory hotspots systematically across the entire proteome, including protein classes that have largely been considered undruggable.

Learn more About Our SpotFinder™ Platform