HotSpot Therapeutics debuts with $45 million to pursue allosteric inhibitors

HotSpot Therapeutics is debuting with $45 million from Atlas Venture and Sofinnova Partners to explore allosteric inhibitors against tough-to-drug targets. The Cambridge, Mass.-based biotech firm will focus on developing small molecules that hit regulatory hotspots, areas on proteins that nature uses to control activity.

Unlike proteins’ active sites, which most conventional drugs target, allosteric sites, or pockets, are involved in protein function. Founded by two former Nimbus Therapeutics executives, HotSpot is tapping into the ways nature uses allosteric sites to turn proteins on and off.

The firm first draws on computational technology to identify pockets that nature uses to regulate proteins. It then probes the value of the pockets by pairing engineered proteins with a library of small molecules designed to bind to the regulatory hotspots.

HotSpot is one of a number of allostery-focused biotech firms to emerge in recent years. Geraldine Harriman, HotSpot’s cofounder and chief scientific officer, sees a few reasons for the interest in looking beyond the active site for drug targets, including new, enabling technology for the discovery of allosteric sites and progress in the clinic for several “super nice” allosteric inhibitors.

And although the up-front work required to find and probe an allosteric site is generally more intensive than for active sites, the resulting molecules tend to translate better into the clinic. That’s because small molecules targeting active sites compete with the protein’s natural ligand—which becomes clear during in vivo testing.

“With most typical drug discovery programs, the minute you go from the enzyme to the cell, the potency can drop by 1,000-fold,” says HotSpot cofounder and CEO Jonathan Montagu.

HotSpot executives say their focus on regulatory hotspots differentiates the company from others working on allosteric inhibitors. “It’s not just any pocket; it’s the specific pocket that nature uses to control the protein,” Harriman explains.

The biotech firm says it has already identified regulatory hotspots for 100 drug targets spanning classes that include kinases, proteases, phosphatases, and targets without active sites, such as transcription and translation factors.

Its most advanced programs involve allosteric inhibitors of the metabolic enzyme S6 kinase (S6K), a target relevant in nonalcoholic steatohepatitis (more commonly known as NASH), and the autoimmune target PKC-theta.

Both are well-studied proteins that researchers have so far failed to inhibit with drugs. In the case of S6K, “Novartis and Pfizer spent a lot of time and energy trying to drug that target,” Montagu says. But the active site is strikingly similar to those of other closely-related enzymes, making it tough to come up with selective molecules.

HotSpot has identified molecules that target a part of the protein that has thus far never been broached, yielding what Montagu says are the “first and only allosteric inhibitors” against S6K. HotSpot anticipates identifying lead compounds for the two programs by early 2019.