Exploring the journey of a mitochondrial complex I inhibitor from laboratory discovery to clinical trials and beyond
Imagine microscopic power plants inside every cell of your body, working tirelessly to convert food into energy—these are our mitochondria. For decades, cancer researchers have been fascinated by how cancer cells hijack these cellular power plants to fuel their relentless growth.
Unlike healthy cells, many cancers exhibit what's known as the "Warburg effect"—they rely heavily on glycolysis (sugar fermentation) even when oxygen is plentiful.
Emerging research has revealed that certain aggressive cancers instead depend heavily on mitochondrial oxidative phosphorylation (OXPHOS), the most efficient energy-producing pathway in our cells.
IACS-010759 isn't the first complex I inhibitor discovered—natural toxins like rotenone have been known for decades. However, these conventional inhibitors often come with significant toxicity that limits their medical use. What made IACS-010759 special was its unique binding site and properties.
Binds to the middle of the ND1 subunit in the membrane domain of complex I 1
10 times more effective at suppressing reverse electron transfer than forward electron transfer 1
Creates energy depletion and biosynthetic impairment in OXPHOS-dependent cancer cells
One pivotal study that demonstrated the potential of IACS-010759 was conducted by Molina and colleagues, who investigated its effects on OXPHOS-dependent cancer models 1 3 .
| Cancer Type | IC50 Value | Key Metabolic Findings | In Vivo Tumor Response |
|---|---|---|---|
| Brain Cancer | <10 nM | 85% reduction in oxygen consumption | Significant growth inhibition at 10 mg/kg |
| Acute Myeloid Leukemia | 1-10 nM | ATP depletion & aspartate reduction | Tumor regression in 5/8 models |
| Pancreatic Cancer | Variable (1-1000 nM) | 50% growth inhibition in 24/30 lines | Dose-dependent suppression |
Multiple human cancer cell lines, including brain cancer and AML models
OCR and ECAR measurements using specialized metabolic analyzers
Cell viability, proliferation, and apoptotic markers tracking
Comprehensive profiling of metabolic intermediates via mass spectrometry
Mouse models with human tumor xenografts receiving oral IACS-010759
Buoyed by compelling preclinical data, IACS-010759 advanced into two first-in-human phase I clinical trials in 2016-2017 2 .
Population: 17 patients with relapsed/refractory acute myeloid leukemia (AML)
Median Age: 60 years (29-77)
Prior Therapies: Median 4 (1-10)
Population: 23 patients with advanced solid tumors
Median Age: 53 years (23-71)
Prior Therapies: Median 3 (1-9)
For scientists interested in pursuing research on oxidative phosphorylation inhibition, several key reagents and tools are essential:
Function: Potent complex I inhibitor
Specifications: 562.6 Da molecular weight, >98% purity, soluble in DMSO 3
Function: Measure OCR and ECAR in real-time
Application: Key for metabolic phenotyping of cells
Function: Identify binding sites in protein complexes
Example: [125I]IACS-010759-PD1 for complex I mapping 1
Function: In vitro studies of electron transfer
Application: Bovine heart SMPs used in mechanism studies 1
Function: Quantify metabolic changes post-treatment
Application: Mass spectrometry for aspartate, nucleotide measurements
The story of IACS-010759 illustrates both the promise and challenges of targeting cancer metabolism. While the clinical outcomes were disappointing, the experience yielded valuable insights that are shaping next-generation approaches:
The narrow therapeutic index suggests that moderate inhibition might be more viable than complete shutdown 4 .
Research continues into using OXPHOS inhibitors as radio-sensitizers rather than standalone therapies 4 .
Scientists are exploring triphenylphosphonium (TPP+) conjugates that preferentially accumulate in mitochondria of cancer cells 4 .
Identifying reliable predictors of OXPHOS dependency remains crucial. MCT4 expression has emerged as a potential biomarker 6 .
The rise and fall of IACS-010759 as a standalone therapeutic shouldn't be viewed as a failure but rather as an important chapter in the evolving story of cancer metabolism research. Each clinical setback provides invaluable insights that refine our approach, moving us closer to effectively targeting cancer's metabolic vulnerabilities without harming patients.