Therapeutics · Obesity and metabolic disease
Equator Therapeutics
A preclinical drug company in St. Louis trying to raise the body’s calorie burn by opening a controlled proton leak inside mitochondria. Two Nature papers, four NIH grants, no trials, and a safety problem its own grant application states in blunt terms.
The current nobody had recorded
A mitochondrion is about a micron across. To press a glass pipette against its inner membrane and measure the current crossing it, the way physiologists have patched nerve cells for half a century, somebody first has to strip the organelle down and hold it still.
Yuriy Kirichok’s laboratory at the University of California, San Francisco worked out how, and that method is the foundation of everything Equator Therapeutics is built on. The company says so in its own words: “In an experimental tour de force, we measured the tiny electrical currents that mitochondria use to generate heat.”
What the recordings showed, published in Nature in July 2019 with Kirichok as senior author, was that a protein famous for one job had a second one. The mitochondrial ADP/ATP carrier, or AAC, trades cellular ATP for ADP. The patch clamp revealed it also carries protons across the membrane when long chain fatty acids are present, and that proton traffic is not wasted. It comes out as heat.
That is thermogenesis: the trick brown fat uses to keep newborns warm, running in ordinary tissue. The paper says AAC “connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.” Nudge that proton door open on purpose and a person burns more calories sitting still.
Why nobody had done it already
They had, and it went badly. Chemicals called protonophores force protons through membranes indiscriminately, and one of them, 2,4-dinitrophenol, was sold as a weight loss drug in the 1930s. It worked. The FDA drove it off the market in 1938 after severe toxicity and deaths, and it is still banned for human consumption.
The reason is a margin problem, not a mechanism problem. Poison Control puts it in one line: “There is very little difference between a therapeutic dose and a toxic or lethal dose.” Overheating and cardiovascular collapse follow, and there is no antidote.
Equator’s second Nature paper, in June 2022, explains the old poison in terms of the new target. Kirichok’s group recorded the proton currents that DNP and related uncouplers induce and found they run through AAC and through uncoupling protein 1. The old drugs were hitting the right door by accident, along with every other membrane in the cell. The paper frames its finding as a starting point, “paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.”
That is the company thesis: hit the door on purpose, and nothing else.
A mathematician, a biophysicist and a cell biologist
Jonah Sinick, the co-founder and chief executive, has a doctorate in mathematics from the University of Illinois and came to biology through data. He was head of data science at BioAge Labs, where, by his company bio, he built the platform that “served as the basis for BioAge’s progress through Series B.”
Kirichok, the co-founder and chief scientific officer, stayed a UCSF professor. Liliya Gabelev Khasin, the third co-founder, was principal investigator on the company’s first federal grant. Simon Vu, a pharmacology and toxicology PhD from UC Davis, is principal scientist and now runs the grants. Katherine Widdowson heads medicinal chemistry.
The advisory bench is heavier than the payroll, which is six people by PitchBook’s count: Gerald Shulman of Yale, Andrea Dunaif of Mount Sinai, UCSF computational chemist Michael Grabe, who is also a co-author on the 2022 Nature paper, and John Amatruda, who ran diabetes and obesity research at Merck.
The turn from full agonist to partial agonist
Between 2021 and 2026 the National Institute of Diabetes and Digestive and Kidney Diseases put $3,905,941 into the company across four SBIR awards. Those applications are public, and they are the most candid document trail Equator has produced.
Phase I screened roughly 67,000 small molecules and returned four chemically distinct leads that selectively activate proton leak through AAC. The company reported that “one of our partially optimized compounds can increase energy expenditure and cause weight loss in diet-induced obesity (DIO) mice.” Mice, not people. Phase II, running to June 2026, aimed those compounds at rodent efficacy and at studies that would enable an investigational new drug application.
Then the September 2026 application changed the plan. It names the lead compound EQ-1 and describes it as the first selective activator of proton leak through AAC. It also says this: “However, EQ-1 is a full AAC agonist, and the large H+ leak activated by EQ-1 can overstimulate thermogenesis, risking overheating and ATP depletion at higher doses.”
That is the DNP failure mode arriving at a selective drug by a different road. The answer is to stop trying to open the door all the way. A new series, EQ-A, is built from partial agonists that produce a smaller maximum proton current, capping the thermogenic response by design. The stated bar is high: “An ideal drug designed to safely increase energy expenditure should exhibit minimal toxicity even in cases of substantial overdose.”
What is proven, and what is still claimed
| Evidence | What the record shows | Source type |
|---|---|---|
| Target identification | Bertholet et al., Nature, July 2019. Patch clamp of inner mitochondrial membranes from mouse tissues identified two AAC transport modes, ADP/ATP exchange and fatty acid dependent H+ transport. Kirichok is senior author. | Public record |
| Mechanism of old uncouplers | Bertholet et al., Nature, June 2022. DNP, FCCP and other protonophores were shown to induce proton leak through AAC and UCP1. Co-authors include Equator advisor Michael Grabe. | Public record |
| Animal efficacy | Reported in the Phase II SBIR application: one partially optimized compound increased energy expenditure and caused weight loss in diet-induced obese mice. No paper or dataset found. | Public record |
| EQ-1 safety margin | The FY2026 application states EQ-1 is a full AAC agonist whose large proton leak can overstimulate thermogenesis, with risk of overheating and ATP depletion at higher doses. EQ-A partial agonists are the stated fix. | Public record |
| “Without side effects” | The Y Combinator profile says the platform finds compounds that selectively activate the target “without side effects.” The company’s own 2026 grant application describes an overheating and ATP depletion risk for its lead compound. | Differs from the record |
| Clinical trials | No study sponsored by Equator Therapeutics on ClinicalTrials.gov as of Sep 23, 2026. No IND disclosed, and no FDA record, as expected preclinically. | Not found |
| Federal grants | Four NIDDK SBIR awards: $340,882 (FY2021), $1,571,137 (FY2024), $1,571,137 (FY2025), $422,785 (FY2026). Total $3,905,941. | Public record |
| Patents | PitchBook lists three pending applications titled “Compositions and methods for treating metabolic disorders,” first filed Mar 11, 2024 and Sep 13, 2024. Not read directly; patent office retrieval was blocked. | Data provider |
| Where it actually is | The company footer and PitchBook give 4340 Duncan Ave, St. Louis, MO 63110, and NIH RePORTER lists Saint Louis on all four awards. Y Combinator, Crunchbase and CB Insights still list San Francisco. | Public record |
Read plainly: the biology is real, published in Nature twice, and the target is specific in a way the 1930s chemistry never was. What has not happened is a human being. Everything on the efficacy side is mouse data described inside grant applications rather than in a journal, no compound has been named in a trial registry, and the company has revised its lead program once already on safety grounds it identified itself. That last fact counts in its favour, and it is also the reason to read the “without side effects” line on the Y Combinator page as marketing rather than a finding.
What to watch
- Whether EQ-A partial agonists clear the toxicity work in the FY2026 grant, which runs to August 2027.
- A peer reviewed paper with the mouse energy expenditure and weight data. None has appeared.
- Any IND filing or first registered trial. Nothing is on ClinicalTrials.gov today.
- Published patent applications, which would show the chemical series rather than its title.
- A priced venture round. Disclosed equity is small next to the grant money.
In their words
“In an experimental tour de force, we measured the tiny electrical currents that mitochondria use to generate heat.”
Equator Therapeutics website, accessed Sep 2026 · Company
“Equator Therapeutics’ co-founders identified this protein as the mitochondrial ADP/ATP carrier (AAC) enabling the first targeted approach in controlling mitochondrial thermogenesis in humans.”
NIH SBIR application 1R43DK146576-01A1, FY2026 · Public record
“However, EQ-1 is a full AAC agonist, and the large H+ leak activated by EQ-1 can overstimulate thermogenesis, risking overheating and ATP depletion at higher doses.”
NIH SBIR application 1R43DK146576-01A1, FY2026 · Public record
“An ideal drug designed to safely increase energy expenditure should exhibit minimal toxicity even in cases of substantial overdose.”
NIH SBIR application 1R43DK146576-01A1, FY2026 · Public record
“Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.”
Bertholet, Kirichok et al., Nature, June 2022 · Peer reviewed
“There is very little difference between a therapeutic dose and a toxic or lethal dose.”
Wendy Klein-Schwartz, clinical toxicologist, Poison Control, on DNP, 2025 · Independent
“It was remarkably effective but was eventually banned due to its severe toxic effects.”
Tristan Rawling, University of Technology Sydney, on DNP, News-Medical, Dec 2025 · Independent
Related companies
Sources
- Public recordNIH RePORTER, 1R43DK146576-01A1, Partial Agonism of Mitochondrial Thermogenesis for the Safe Stimulation of Energy Expenditure
- Public recordNIH RePORTER and SBIR.gov, R43DK127880 and R44DK127880, New Generation of Mitochondrial Uncouplers for the Treatment of Metabolic Disorders
- Public recordH+ transport is an integral function of the mitochondrial ADP/ATP carrier
- Public recordMitochondrial uncouplers induce proton leak by activating AAC and UCP1
- Public recordClinicalTrials.gov searches for Equator Therapeutics, no sponsored study found
- IndependentDon’t believe social media: DNP is not safe
- Data providerEquator Therapeutics company profile, funding, patents and investors
- CompanyEquator Therapeutics website: science, team, advisors and founder bios
- CompanyEquator Therapeutics company profile, Winter 2020 batch
Profile researched and written by Healthcare Discovery. Last updated September 29, 2026.
