In real estate, location is key. The same holds true in the hunt for new drugs. HotSpot Therapeutics is trying to break new ground in drug discovery by hitting locations on a protein that aren’t the conventional targets of most medicines.
HotSpot is now emerging from stealth with preclinical compounds that could become new treatments for liver disease and autoimmune disorders. As the Cambridge, MA, biotech works to bring its lead drugs into human testing, the company is also unveiling $45 million to finance its efforts.
“We’re uncovering very new biological space and then marrying that with new chemistry,” says HotSpot co-founder and CEO Jonathan Montagu (pictured above, left). “It’s chemistry meets biology in a very new way.”
A drug works by binding to a protein and either sparking activity or blocking it. Most drug discovery focuses on finding compounds that target what’s called the “active site”—the location where a protein binds to another molecule and causes a chemical reaction. But these sites are small and they’re hard to hit, Montagu says. A drug that binds to an active site can also lead to side effects, as a molecule meant to inhibit one protein may also block others in the same family of proteins.
HotSpot is developing drugs that bind to a protein at allosteric sites, which are places elsewhere on the protein besides the active site. Binding to these other sites can still spark activity in the protein. One example of allostery in action in the human body is hemoglobin, the oxygen-carrying blood protein. When an oxygen molecule binds to a non-active site on hemoglobin, it causes other locations of the protein to become more receptive to oxygen molecules. That means hemoglobin is able to deliver more oxygen to the tissues of the body.
The HotSpot technology, SpotFinder, finds non-active sites and helps the company’s scientists understand how these sites regulate a protein, says Geraldine Harriman (pictured above, right), HotSpot’sco-founder and chief scientific officer. After identifying a potential target, the technology validates it. SpotFinder then screens HotSpot’s chemical libraries to identify drug candidates to hit those locations. Harriman adds that SpotFinder can also find allosteric “hotspots” on proteins that don’t have active sites. That means that the technology has the potential to broaden the scope of diseases treatable with drugs. Harriman calls it “new biological real estate with new chemical approaches.”
“We like to see it as a form of smart and intelligent allostery,” she says. “We’re going after the sites that nature uses to control the function of the proteins.”
Montagu says an allosteric approach to drug discovery could lead to medicines that are
