HotSpot Therapeutics Emerges From Stealth Mode With $45 Million to Aim at New Biological Targets

Drug Discovery

Cambridge, Mass.-based HotSpot Therapeutics burst forth from stealth mode with $45 million in Series A funding to support the development of therapies that will target natural “regulatory hotspots.”

The company, which was founded by Nimbus Therapeutics veterans Jonathan Montagu and Geraldine Harriman, defined those regulatory hotspots as a “unique family of allosteric sites used by nature to regulate protein function.” HotSpot aid it is the first company to “systematically harness” these sites for drug discovery. Regulatory hotspots are “unique pockets on a protein, located remotely from the active site, that are both essential for protein function and entirely unique to each target,” the company said. 

By targeting those hotspots, Montagu, Hotspot’s co-founder and chief executive officer said the company can create medicines that work through that same evolutionary mechanism and offer the “same degree of precision and potency.”

HotSpot said it has identified regulatory hotspots in more than 100 proteins. Those hotspots span many pathways and disease of pharmaceutical interest, the company said. HotSpot intends to aim its technology for a first-wave of pipeline agents that target PKC-theta, which plays an important role in multiple autoimmune diseases, and S6 kinase, a metabolic enzyme involved in regulating hepatic insulin sensitivity and mitochondrial function. The company said these are important targets for various disease including nonalcoholic steatohepatitis (NASH), as well as metabolic, and mitochondrial diseases.

 “Regulatory hotspots offer a privileged subset of allosteric sites that remain unexplored for drug discovery and represent a major opportunity to create first-in-class medicines across multiple disease areas,” Montagu said in a statement.

The company used a special technology platform to identify, validate, and design novel chemistries targeting regulatory hotspots. Called SpotFinder, HotSpot’s proprietary technology integrates “structural, druggability, and functional insights to uncover proteins with regulatory hotspots.” Tailored chemical probes and engineered proteins are then used to validate the role of the hotspot site, the company said. The company then screens its bespoke chemical and fragment libraries to create novel drug candidates that target the regulatory hotspots.

Harriman, HotSpot’s chief scientific officer, said the company has the “first and only technology platform” to identify the regulatory hotspots across the entire proteome.

“We then apply novel chemistry to design the first small molecules targeting the hotspot. For proteins without active sites, regulatory hotspots may offer the only way to rationally drug the target.  This allows us to expand the breadth of disease pathways that are accessible to intervention,” Harriman said in a statement.

HotSpot’s Series A funding was backed by Atlas Venture and Sofinnova Partners.

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