HotSpot Therapeutics, a new drug discovery venture exploring protein regulation, has kicked off with $45 million in series A financing.
Co-founded by Nimbus veterans Geraldine Harriman and Jonathan Montagu, HotSpot is targeting the allosteric mechanisms used by the body to control proteins, and developing drugs that bind to unique locations outside enzymes’ active sites in order to regulate their function.
The approach showed success at Nimbus, the former Fierce 15 winner that developed an allosteric inhibitor for nonalcoholic steatohepatitis, later acquired by Gilead in a $1.2 billion deal. The drug, targeting acetyl-CoA carboxylase, demonstrated reductions in liver fat in a phase 2 trial last October.
In addition, the funding round was co-led by Nimbus-backer Atlas Venture, alongside 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,” said Atlas partner Bruce Booth, co-founding investor and chairman of HotSpot.
“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,” Booth added.
So far, the Cambridge, Massachusetts-based HotSpot says it has identified families of unique, allosteric binding sites—the so-called regulatory hotspots—in over 100 proteins across a range of pathways and diseases.
"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 Montagu, a previous Atlas executive-in-residence who lead Nimbus’ business development and operations, and currently serves as HotSpot’s CEO.
"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.
One of HotSpot’s lead small-molecule compounds targets S6 kinase, a metabolic enzyme that helps regulate hepatic insulin sensitivity and mitochondrial function, and could provide a new target for NASH and metabolic diseases. Another is aimed at PKC-theta, which plays roles in several autoimmune diseases, and enhances regulatory T-cells while inhibiting effector T-cell responses.
Conventional drug discovery methods targeting proteins’ active sites have, at times, been limited been limited in selectivity and druggability.
"At HotSpot, we have developed the first and only technology platform to identify regulatory hotspots systematically across the entire proteome," said Harriman, who serves as chief scientific officer.
"For proteins without active sites, regulatory hotspots may offer the only way to rationally drug the target,” she said. “This allows us to expand the breadth of disease pathways that are accessible to intervention.” Harriman previously lead Nimbus’ NASH development subsidiary, Apollo, before it was bought by Gilead.
“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," said Sofinnova’s Graziano Seghezzi.
"Given the team's proven track record, we were not surprised to see HotSpot make incredible progress in a very short period of time,” said Seghezzi, a co-founding investor who sits on the board. “In just over 12 months, the team delivered the first and only hotspot allosteric inhibitors for a series of important but previously undrugged targets.”