Natural spots

HotSpot Therapeutics’ small molecules take a page from natural allostery

With a new take on allosteric modulation, HotSpot Therapeutics Inc. has emerged from stealth mode to find specialized niches on proteins that nature uses to control their activity. The company’s platform has identified druggable allosteric sites on more than 100 targets, including transcription factors and other proteins that lack active sites.

On July 17, HotSpot announced that it completed a $45 million series A round co-led by Atlas Venture and Sofinnova Partners. The company plans to nominate two lead candidates by early next year.

The common approach to inhibiting cellular pathways is to focus on the active sites of key enzymes, and create compounds that block them directly. But the strategy runs into problems when the sites are highly similar among different enzymes, making it difficult to find specific drugs, and for other therapeutically relevant proteins without active sites.

“We as an industry always try to put something in the active site,” said co-founder and CEO Jonathan Montagu. “HotSpot wants to understand how nature controls proteins and mimic that” with tailor-made compounds.

Although allostery isn’t new to drug development, co-founder and CSO Geraldine Harriman said that drug discovery has typically relied on unbiased screening.

“Most allosteric inhibitors were identified through broad phenotypic screening, and then later found to be allosteric in nature,” she said.

HotSpot has built a systematic approach. The newco uses its computational platform SpotFinder to identify proteins with allosteric sites -- called

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