He spent years closing other people's biotech deals. Then he decided to build the company he'd actually want to buy - one that goes after the protein sites everyone else filed under undruggable.
Most drugs grab a protein by the obvious handle - the active site, the slot where the enzyme does its work. Jonathan Montagu builds medicines that reach past the handle and press on the switches underneath. HotSpot Therapeutics, the Boston company he co-founded in 2017, calls those switches "natural hotspots": pockets evolution spent millions of years carving into proteins to turn them up, down, on, off. Find one, fit a small molecule into it, and you can steer a protein the way nature does. That is the whole bet, and it is not a small one.
For decades the industry drew a line between targets it could drug and targets it couldn't. The undruggable list was long and demoralizing. Montagu's thesis is that the list was never a law of physics. It was a failure of imagination about where to push. "HotSpot is targeting natural regulatory sites on proteins that evolution has perfected over many millions of years," he has said. "This allows us to create medicines that work through exactly the same mechanisms, offering the same degree of precision and potency."
HotSpot's platform has a name - Smart Allostery - and a job: scan a protein for the pockets that actually decide its behavior, then design molecules that occupy them. The payoff is precision. Conventional programs lose potency the moment a compound leaves the test tube for a living cell. Montagu puts the drop-off bluntly: "With most typical drug discovery programs, the minute you go from the enzyme to the cell, the potency can drop by 1,000-fold." Targeting a regulatory site that the cell already respects is his way around that cliff.
By 2024 the thesis had left the slide deck. HotSpot presented first-in-human Phase 1 data on HST-1011, an oral CBL-B inhibitor aimed at switching the immune system back on against cancer, at the ESMO Congress. CBL-B is one of those brakes the body uses to keep immune cells in check; release it in the right place and T cells get back to work. Getting a small molecule to do that selectively is exactly the kind of problem HotSpot was built to solve. Alongside oncology, the company runs an autoimmune program - the same switches, turned the other direction.
The resume reads in two halves, and the seam is the interesting part. The first half is a chemist's. Montagu trained at Oxford under Jack Baldwin, did research at The Scripps Research Institute with K.C. Nicolaou, spent time at Cold Spring Harbor Laboratory, and worked at Cancer Research UK under Paul Nurse - the Nobel laureate who helped crack how cells divide. Three of the biggest names in chemistry and cell biology, before he had ever run anything.
Then he changed lanes. An MBA from Stanford's Graduate School of Business pointed him toward the business side of biotech, where the real bottleneck is rarely the chemistry alone - it's capital, partnerships, and the patience to fund a decade of work. At Concert Pharmaceuticals he ran business development and helped secure a $1B multi-product transaction with GSK. At Nimbus Therapeutics he served as Chief Business Officer, helping build the drug discovery platform and closing deals with Gilead, Shire and Monsanto. He learned, deal by deal, what a discovery engine is worth and what it takes to keep one running.
HotSpot is what happens when those two halves fuse. A founder who can read a crystal structure and a term sheet with equal fluency is a rare animal, and it shows in how the company has been funded and steered. He co-founded it with Geraldine Harriman, PhD, a medicinal chemist, pairing platform science with the operator's discipline he'd spent a career absorbing.
HotSpot launched in 2018 with a $45M Series A and the Nimbus pedigree behind it. The capstone so far is the 2021 Series C: an oversubscribed $100M round led by Pivotal bioVenture Partners, with LSP, B Capital Group, Atlas Venture, Sofinnova Partners and a roster of healthcare and tech investors piling in. The point of that money, in Montagu's framing, was to expand on the platform's productivity and carry it into the clinic. Total funding now sits around $210M.
Montagu doesn't only run HotSpot. He serves as a Non-Executive Director at OMass Therapeutics and as an advisor at Atlas Venture, the firm that helped seed his company. It's a familiar shape in Boston biotech - the founder who stays plugged into the ecosystem that made him, lending pattern recognition to the next round of teams trying to do the hard, slow thing.
What's striking about how he talks is what he leaves out. There's little founder mythology, few claims of lone genius. He calls the protein sites he chases "biological real estate" - the prime locations nature already optimized - and he keeps returning to the team. The most quotable thing he says is also the least glamorous: it takes everyone to build a biotech and develop a drug. For a man who could lean on three legendary mentors and a billion-dollar deal as his calling card, that's a deliberately unglamorous way to describe the work.
The verdict is still out, the way it always is in drug development, where the clock runs in years and most bets quietly fail. But the shape of the wager is clear. Montagu looked at a problem the industry had circled for decades, decided the obstacle was a habit and not a wall, and built a company around the parts of proteins everyone else had given up on. The clinic will settle the rest.
Three rounds, one thesis. The money tracks the moment HotSpot moved from a bet about protein pockets to drugs in human beings.
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.
With most typical drug discovery programs, the minute you go from the enzyme to the cell, the potency can drop by 1,000-fold.
He calls the protein pockets HotSpot targets "biological real estate" - the prime spots evolution already optimized.
Trained under a Nobel laureate, Paul Nurse, before he had ever run a company.
His career splits cleanly in two: academic chemist, then billion-dollar dealmaker. HotSpot is the seam.
Co-founded the company with medicinal chemist Geraldine Harriman, PhD - science paired with operations.
Still advises Atlas Venture, the firm that helped seed his own company.
His most-repeated line is also his least flashy: "It takes everyone to build a biotech."