# New Generation of Mitochondrial Uncouplers for the Treatment of Metabolic DIsorders

> **NIH NIH R44** · EQUATOR THERAPEUTICS, INC. · 2024 · $1,571,137

## Abstract

Summary
 Effective treatments for obesity have been a major need for decades, as the high prevalence of obesity
and associated metabolic disorders has continued to rise. To achieve weight loss, obesity treatments must
either decrease energy intake or increase energy expenditure. GLP-1 receptor agonists have recently emerged
as the first effective drugs that decrease energy intake by reducing appetite. While these drugs are promising,
the need for alternative and complimentary treatments persists due to reported variations in their efficacy and
suboptimal effects on body composition. Equator Therapeutics is developing a first-in-class drug to increase
energy expenditure. Specialized thermogenic reactions within mitochondria form the only known energy
expenditure pathway that can be safely controlled without negatively impacting other essential physiological
processes. Mitochondrial thermogenesis depends on H+ leak across the inner mitochondrial membrane
mediated by mitochondrial uncoupling proteins (UCPs). In vivo, UCPs are activated by long-chain fatty acids
(LCFAs). In humans, skeletal muscle plays a dominant role in adaptive non-shivering thermogenesis. The UCP
responsible for mitochondrial thermogenesis in skeletal muscle and its pharmacological control long remained
elusive until Equator’s scientific co-founders developed a method to directly measure mitochondrial H+ leak
using the patch-clamp technique and demonstrated that the LCFA-induced H+ leak in skeletal muscle is
mediated by the mitochondrial ADP/ATP carrier (AAC) (Bertholet et al, Nature 2019). They also identified likely
AAC binding sites for LCFAs and small-molecule activators of H+ leak (Bertholet et al, Nature 2022). Based on
this work, we are developing small-molecule activators of H+ leak via AAC that mimic the thermogenic effect of
LCFAs but offer high oral bioavailability.
 In the Phase 1 SBIR, we developed a high-throughput drug discovery funnel and identified four
chemically unique lead molecules that selectively activate H+ leak via AAC. We also demonstrated that one of
our partially optimized compounds can increase energy expenditure and cause weight loss in diet-induced
obesity (DIO) mice. In this Phase 2 application, we propose to carry out further medicinal chemistry
optimization of these lead compounds and to test optimized analogs for efficacy and safety in DIO rodent
models. The proposal has three specific aims. In Aim 1 we will optimize our compounds to increase in vivo
potency and maintain good exposures with chronic dosing. The optimized lead compounds will then be
advanced to in vivo efficacy studies in Aim 2, where we will demonstrate that they increase the metabolic rate
in DIO rodent models and determine safe doses for use in subsequent weight-loss studies. Finally, in Aim 3,
we will determine the efficacy of the optimized lead compounds for treating obesity, type 2 diabetes, and fatty
liver disease in DIO rodents. Successful completion of this proposal will ...

## Key facts

- **NIH application ID:** 10922344
- **Project number:** 2R44DK127880-02A1
- **Recipient organization:** EQUATOR THERAPEUTICS, INC.
- **Principal Investigator:** Simon Vu
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,571,137
- **Award type:** 2
- **Project period:** 2021-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922344

## Citation

> US National Institutes of Health, RePORTER application 10922344, New Generation of Mitochondrial Uncouplers for the Treatment of Metabolic DIsorders (2R44DK127880-02A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10922344. Licensed CC0.

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