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 charge and greasiness 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 and treat previously inaccessible diseases.

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

Potent in vivo pharmacology. Hotspot inhibitors do not compete with substrate in the context of the cell.

Attractive drug-like characteristics. Hotspots allow chemists to exploit a range of new molecular scaffolds (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

Regulatory hotspots in disease

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:

Acetyl CoA Carboxylase (ACC)

  • Natural function: critical enzyme in fatty acid metabolism

  • Disease setting: used to calibrate fat synthesis to energy needs of the cell

  • Regulatory hotspot: in metabolic diseases such as NASH (Non-alcoholic steatohepatitis), inhibition of ACC has been shown to reduce hepatic fat content, inflammation and fibrosis

  • Medicine: highly-selective hotspot inhibitors mimic regulatory region; low dose, slow off rate, phase 2a proof of concept

Bcr-abl

  • Natural function: master control of cell proliferation and differentiation

  • Disease setting: oncogenic fusion creates Bcr-abl in chronic myelogenous leukemia (CML)

  • Regulatory hotspot: used to autoinhibit enzyme, thereby limiting activity to key
    settings

  • Medicine: Hotspot inhibitors mimic effect of regulatory tail in the hotspot. Opportunity for first clinical cures of CML when dosed in combination with active site inhibitors

HotSpot Therapeutics has designed the first and only Technology Platform to identify and drug regulatory hotspots systematically across the entire proteome.