Partial agonism of mitochondrial thermogenesis for the safe stimulation of energy expenditure

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Equator Therapeutics, Inc., $422,785 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to develop selective partial agonists of the mitochondrial ADP/ATP carrier (AAC) as a novel approach to weight loss and metabolic health.

Equator Therapeutics is developing a class of partial AAC agonists designed to safely increase energy expenditure through stimulation of mitochondrial thermogenesis, an alternative mechanism to current GLP-1 receptor agonist therapies. The company identified AAC as the protein mediating proton leak across the inner mitochondrial membrane in humans and is now engineering partial agonists that activate smaller proton leak currents than its lead compound EQ-1, reducing the risk of overheating and ATP depletion at higher doses while maintaining therapeutic efficacy for weight loss and metabolic disorder treatment.

Work is performed in St. Louis, Missouri, with a period of performance from September 1, 2026, through August 31, 2027. This is a Phase I SBIR project grant, the assistance type supporting early-stage innovation in small businesses for applied research with commercial potential.

Abstract

Weight loss medications have enormous potential to improve metabolic and cardiovascular health for up to 50% of the US population. Current treatments, such as GLP-1 receptor agonists, effectively reduce body weight through suppression of food intake. However, these drugs have important limitations, including loss of lean mass, gastrointestinal side effects leading to poor adherence, and inadequate weight loss in many patients. Crucially, these therapies do not address energy expenditure, another powerful mechanism that regulates weight. A therapy that increases energy expenditure could overcome these limitations of GLP-1 receptor agonists, greatly improving on the standard of care. Energy expenditure can be elevated through stimulation of mitochondrial thermogenesis, a process mediated by proton (h⁺) leak across the inner mitochondrial membrane (IMM). However, selective pharmacological stimulation of mitochondrial thermogenesis was hampered by the fact that the protein responsible for mitochondrial h+ leak in adult humans was unknown. 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. This discovery facilitated the development of EQ-1, the first selective activator of mitochondrial h⁺ leak via AAC. 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. An ideal drug designed to safely increase energy expenditure should exhibit minimal toxicity even in cases of substantial overdose. To achieve this crucial safety profile, equator therapeutics has identified a novel class of selective partial AAC agonists (PAS), which activate significantly smaller h⁺ leak currents via AAC than EQ- 1 does, reducing the maximal thermogenic response, and inherently avoiding the risks associated with full AAC agonists. In this sbir proposal, we aim to optimize a PA series called EQ-a and rigorously evaluate the most promising compounds of this series, through the following specific aims: aim 1: optimize EQ-a partial agonists for improved oral exposure. Aim 2: assess the toxicity of partial agonists in vitro and in vivo. Aim 3: determine the efficacy of partial agonists in increasing metabolic rate and reducing weight in mice. These studies will provide key preclinical data on EQ-a's safety and therapeutic potential, supporting the development of a transformative energy expenditure-based obesity treatment.