HotSpot Therapeutics, a new biotechnology company targeting nature's regulatory hotspots to discover and develop first-in-class medicines, today announced the completion of a $45 million Series A financing. "Regulatory hotspots" are a unique family of allosteric sites used by nature to regulate protein function and HotSpot is the first company to systematically harness these sites for drug discovery.

"HotSpot is targeting natural regulatory sites on proteins that evolution has perfected over many millions of years. This allows us to create medicines that work through exactly the same mechanisms, offering the same degree of precision and potency," said Jonathan Montagu, CEO and co-founder of HotSpot Therapeutics. "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."

New Approach to Allosteric Drug Discovery

Conventional drug discovery involves targeting the active site of a protein to control protein function and has been limited in its ability to address many diseases safely and effectively. In contrast, 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. As a result, molecules designed to target regulatory hotspots are highly selective and potent.

"At HotSpot, we have developed the first and only technology platform to identify regulatory hotspots systematically across the entire proteome. We then apply novel chemistry to design the first small molecules targeting the hotspot," said Geraldine Harriman, PhD., Chief Scientific Officer and co-founder. "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."

First and Only Technology Platform for Regulatory Hotspots

A specialized technology platform enables HotSpot to identify, validate, and design novel chemistries targeting regulatory hotspots. HotSpot's proprietary SpotFinder 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. Finally, HotSpot's bespoke chemical and fragment libraries are screened, using state-of-the-art computational and biophysics techniques, to generate novel drug candidates targeting regulatory hotspots. Each step in the process involves technologies or capabilities that have been custom designed for hotspot drug discovery.

Backed by Atlas Venture and Sofinnova Partners

"HotSpot's elegant and systematic approach to allostery, focused uniquely on regulatory hotspots, sets it apart from everything else we have seen in the field. From the outset, we knew that regulatory hotspots were critical to protein function and now we see vividly that the known footprint of the natural protein ligand accelerates our chemistry efforts," said Bruce Booth, DPhil, Chairman of HotSpot Therapeutics and co-founding investor. "HotSpot is changing the way allosteric drug discovery is conducted in a profound way and Atlas is very excited about the launch of this company."

To date, HotSpot has identified regulatory hotspots in over 100 proteins spanning many pathways and diseases of pharmaceutical interest. The company's first wave of pipeline agents include novel compounds targeting 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 and an important new target for NASH, metabolic, and mitochondrial diseases.

"The HotSpot team had previously pioneered turning regulatory hotspots for specific targets into development-stage medicines. Now they are well-positioned to systematically scale up and apply this new type of drug discovery to a large number of drug targets," commented Graziano Seghezzi, HotSpot Director, Partner at Sofinnova Partners, and co-founding investor. "Given the team's proven track record, we were not surprised to see HotSpot make incredible progress in a very short period of time. In just over 12 months, the team delivered the first and only hotspot allosteric inhibitors for a series of important but previously undrugged targets."

HotSpot has assembled an experienced team of scientists and industry experts with a strong track record of bringing new thinking to complex drug discovery challenges. HotSpot was founded in 2017 by Jonathan Montagu and Geraldine Harriman, PhD., following their success at Nimbus Therapeutics with the hotspot-directed ACC program. Its Board of Directors include Bruce Booth, DPhil, Chairman and Partner at Atlas Venture and Graziano Seghezzi, Managing Partner at Sofinnova Partners.

About HotSpot Therapeutics

HotSpot Therapeutics is targeting nature's regulatory mechanisms to create allosteric medicines that exhibit high precision and potency. HotSpot's proprietary SpotFinder technology platform is the first and only technology platform to systematically identify and target "regulatory hotspots" - a unique family of allosteric sites used by nature to regulate protein function. Using bespoke chemistry approaches, HotSpot is developing a pipeline of first-in-class medicines for treatment of serious autoimmune and metabolic diseases. The company has identified over 100 regulatory hotspots across a range of proteins and pathways. HotSpot's lead compounds include the first and only allosteric inhibitors to target PKC-theta, for autoimmune diseases, and S6 kinase, an immunometabolic enzyme involved in the regulation of hepatic insulin sensitivity and mitochondrial function - an important new target for NASH and metabolic diseases. HotSpot has raised $45MM from leading life-science investors including Atlas Venture and Sofinnova Partners. To learn more visit www.hotspotthera.com.

About Atlas Venture

Atlas Venture is a leading biotech venture capital firm. With the goal of doing well by doing good, the company has been building breakthrough biotech startups since 1993. Atlas works side by side with exceptional scientists and entrepreneurs to translate high impact science into medicines for patients. Our seed-led venture creation strategy rigorously selects and focuses investment on the most compelling opportunities to build scalable businesses and realize value. For more information, please visit www.atlasventure.com.

About Sofinnova Partners

Sofinnova Partners is a leading European venture capital firm specialized in Life Sciences. Based in Paris, France, the firm brings together 12 highly experienced investment professionals from all over Europe, the US and China. The firm focuses on paradigm shifting technologies alongside visionary entrepreneurs. Sofinnova Partners seeks to invest as a founding and lead investor in start-ups and corporate spin-offs, and has backed nearly 500 companies over more than 40 years, creating market leaders around the globe. Today, Sofinnova Partners has over €1.5 billion under management. For more information, please visit: www.sofinnova.fr.