Hotspot Therapeutics Inc.'s $45 million in series A money will last three years and "gives us the dry powder to bring the company to the point where we'll start clinical studies" with two lead candidates, co-founder and CEO Jonathan Montagu told BioWorld.

Started with a seed round a year ago in March, the Cambridge, Mass.-based firm targets regulatory hotspots, a family of allosteric sites used naturally to regulate protein function. Co-founder and Chief Scientific Officer (CSO) Geraldine Harriman said the company is asking "what nature is teaching us, and how we can use it effectively in drug discovery." She has experience with hotspots, having led the acetyl-coA carboxylase program at Nimbus Therapeutics Inc., also of Cambridge, Mass., which drew Foster City, Calif.-based Gilead Sciences Inc. to the dealmaking table. In 2016, Gilead acquired Nimbus Apollo Inc., a wholly owned subsidiary of Nimbus, for $400 million up front and $800 million in development-related milestone payments to get the program, which "continues to move nicely through the clinic," she said. (See BioWorld Today, April 5, 2016.)

Although one-off targeting of hotspots has proved successful, the new enterprise is the first to systematically pursue those pockets on proteins, which are located remotely from the active site, essential for protein function, and entirely unique to each target. Key to the approach is a method called Spotfinder, which has three elements. "We look at about 130,000 proteins to find pockets that have the fingerprint of regulatory sites," said Montagu, also previously with Nimbus. A database of about 1 million pockets has been created. Then comes druggability – the system finds those most amenable to the discovery of medicines. Third, Spotfinder deploys a "deep-learning engine," surveying about 30 million publications to extract information on the functions of proteins.

"Ninety percent of [the technology] was developed in-house," he said, although the firm has exclusively licensed some aspects of the platform from non-academic sources. "That gives us tremendous flexibility when it comes to the relationships we have with pharma companies," he noted. Another benefit is that Hotspot owns all rights to platform and programs. "I've never been at a company where you have that at the beginning," said Montagu, active in Boston-area biotech for 15 years. So far, the company has identified regulatory hotspots in more than 100 proteins spanning a range of pathways.

Hotspot's way of working lets the firm "broad-sweepingly survey the proteome and allow the computational platform" to locate where best to focus, said CSO Harriman, also a long-timer in the industry. "We want to prove that these sites matter. We recognize that conventional chemical libraries just don't cover that space well, so we've built chemistry that can enable us to find inhibitors." She calls the method "smart and elegant allostery," as compared to development of allosteric inhibitors in the past, which was done by phenotypic screening.

Founding investors Atlas Venture and Sofinnova Partners co-led the series A round. Bruce Booth, also a co-founding backer of Hotspot, serves as chairman, a role he played at Nimbus. Ten employees work in-house, with 26 outside the company at contract research organizations (CROs) around the world.

"We're big fans of the distributive model," Montagu said. "We have large teams of chemists making the molecules, but if we need more chemists next month, it's very easy to do that."

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, which could be useful in nonalcoholic steatohepatitis and diabetes. "They're neck and neck at the moment," Montagu said, adding they may enter the clinic around the same time.

"Every program that we work on internally has some sort of biomarker that we can look at early in clinical development to get a sense of whether we are modulating the target effectively in the right patient population," he said. "If we wanted to focus on a smaller disease area [than NASH or diabetes], there definitely are ones where we could get proof of mechanism," he said.

Hotspot aims to "drive these medicines forward as far as we can" by itself, though the firm is conducting "a number of ongoing discussions" about would-be partnerships. "You can really get pharma companies excited when you say, 'Hey, this is new in both ways, chemistry and biology.'" Discussions involve potential discovery-stage collaborations based on targets of outside interest and deals built around the two lead programs.

Also in the pipeline are "undisclosed oncology programs that we'll be talking about more next year," he said.

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