IACS-010759 / UT MD Anderson Cancer Center - LARVOL DELTA

Drug development targeting the mitochondrial respiratory chain of Sparganum proliferum: Initial biochemical and drug discovery insights into the enigmatic helminth parasite. (PubMed, PLoS Negl Trop Dis) - "The antimalarial drug atovaquone inhibited complex III at a very low concentration (IC₅₀ 2.2 nM). IACS-010759 potently inhibited complex I (IC₅₀ 16.1 nM), causing worm body swelling, surface destruction, and mitochondrial morphological changes in culture assays. Further investigation of the mitochondrial respiratory chain of S. proliferum to develop targeted candidate drugs is warranted."

Journal • Infectious Disease

Integrative Multi-Omics Analysis Reveals a Mitochondrial-Immune Axis Associated With Neoadjuvant Chemotherapy Response in High-Grade Serous Ovarian Cancer. (PubMed, Adv Sci (Weinh)) - "Notably, Nab-paclitaxel outperformed paclitaxel in promoting B cell-mediated humoral immunity...Pharmacologic inhibition of mitochondrial Complex I with IACS-010759, or genetic silencing of its core subunit NDUFA8, selectively restores carboplatin sensitivity in resistant cells and xenograft models...Clinically, CD19+ B-cell infiltration and NDUFA8 expression are significantly associated with platinum responsiveness and NACT outcome. Together, these findings define immune activation and mitochondrial bioenergetic dependency as dual determinants of chemotherapy response and highlight Complex I-targeted intervention as a rational strategy to overcome platinum resistance in HGSOC."

Journal • Platinum resistant • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

IDH1 mutation reprograms differentiation and therapeutic response to FGF receptor blockade in cholangiocarcinoma (ESMO-GI 2026) - "Ivosidenib (ivo), an IDH1 mutant (mIDH1) inhibitor, significantly reduces 2HG and induces differentiation in leukemia...mIDH1 cells were more sensitive to cisplatin and demonstrated increased responses to FGF19 and mitochondrial inhibitors, including IACS-010759 and metformin...Conclusions Our findings suggest that patients with mIDH1 iCCA would benefit from targeted metabolic and FGFR directed therapies in undifferentiated rather than differentiated cholangiocyte state. Pretreatment with ivo may impair responses to alkylating chemotherapy."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGF19 • FGFR4 • IDH1 • SOX9

MECHANISMS OF RESISTANCE TO BTK INHIBITORS INDEPENDENT OF BTK AND PLCG2 MUTATIONS (EHA 2026) - "Results Seven lines of REC-1 cells that acquired resistance to pirtobrutinib or nemtabrutinib lacked BTK, PLCG2 or other known resistance- associated mutations when analyzed by tNGS (Qi J. et al...Treatment with BTKis ibrutinib or nemtabrutinib, or BTK degrader (BTKd) NX-5948 resulted in suppression of BTK phosphorylation or caused BTK degradation, respectively...Hence, BTKi resistant REC-1 did not show signiIcantly increased sensitivity to OXPHOS pathway inhibitor IACS-10759 either as single drug or in combination with BTKi/BTKd...In addition, the CDK inhibitor dinaciclib demonstrated efIcacy as monotherapy in resistant cells, and its combination with the BTKd NX-5948 showed signiIcant synergistic activity in both wild-type and resistant cells...Summary/Conclusion Dysregulation of the cell cycle contributed to acquired BTKi and BTKd resistance in REC-1 cells in the absence of BTK or PLCG2 mutation. Synergistic effects of CDK inhibitors with BTKd need to be further..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • CASP3 • CASP7 • CCNA2 • CDK1 • PLCG2

Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer. (PubMed, Oncol Res) - "Orthotopic xenograft models were utilized to demonstrate the therapeutic effects of the combined administration of the oxidative phosphorylation (OXPHOS) inhibitor IACS-010759 and the Drp1 inhibitor mdivi-1. The results of this study collectively indicate that mitochondrial dynamics regulate metabolism in sorafenib-resistant liver cancer, which displays an aggressive hybrid metabolic phenotype. Accordingly, the combined targeting of mitochondrial dynamics and metabolism may represent an effective strategy to overcome sorafenib resistance in liver cancer."

Journal • Preclinical • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Targeting Complex I specifically inhibits PDAC metabolic plasticity and metastasis (EACR 2026) - "Result and The initial screening platform and additional in vivo treatment studies identified IACS-010759, an inhibitor of OXPHOS complex I in the electron transport chain, to significantly reduce PDAC metastasis... We identified an inhibitor of OXPHOS complex I to profoundly reduce the metastatic potential of PDAC cells in vivo. Further examination of the metabolically distinct cell subpopulation(s) that drive metastasis and the impact of mitochondria targeting therapy on metastatic progression should provide valuable knowledge on targetable vulnerabilities."

Metabolic Disorders • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

DYSREGULATED INTRACELLULAR CHOLESTEROL MEDIATES CHEMOTHERAPY RESISTANCE IN PERSISTENT LEUKEMIA STEM CELLS IN VIVO (EHA 2026) - "To isolate the drivers of resistance, we utilized patient- derived xenograft (PDX) models subjected to in vivo treatment with intensive chemotherapy (AraC+Daunorubicin), the OxPHOS complex I inhibitor IACS-010759 (IACS), or combination of the two. Finally, we will present data on the relapse-free survival of AML patients stratified by statins intake. Targeting cholesterol sequestration may provide a novel rational dual-targeting strategy to eradicate the persistent LSC reservoir and prevent or overcome LSC-mediated relapse in AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • DNMT3A • NPM1

Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia. (PubMed, Biochem J) - "Using the Complex I inhibitor IACS-010759 as a case study, we discuss why systemic ETS inhibition predictably collided with dose-limiting toxicity. Finally, focusing on AML, we dissect how OxPhos 'dependency' was inferred from indirect assays, how the failure to normalize for mitochondrial content may invert conclusions, and how ATP synthase reversal can masquerade as 'ATP-linked respiration.' We conclude with practical criteria for identifying mitochondrial liabilities that are targetable rather than merely essential, and we outline alternative strategies, which may better align mitochondrial biology with a realistic therapeutic index."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

ICAM2 promotes endocrine resistance via dynein-mediated OXPHOS activation in ER-positive breast cancer. (PubMed, Cell Death Dis) - "Therapeutically, combining the complex I inhibitor IACS-10759 with fulvestrant potently inhibited both tumor growth and metastasis. ICAM2⁺ cancer cells-enriched in treatment-resistant tumors-maintain elevated OXPHOS by assembling a functional complex with dynein and mitochondrial Complex I, thereby promoting mitochondrial trafficking. Disruption of this axis, either through ICAM2 depletion or Complex I inhibition, re-sensitizes tumors to therapy, revealing a targetable metabolic dependency in resistant disease."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

RNF43 Deficiency Activates YBX1-MYC-Driven Oxidative Phosphorylation in Pancreatic Cancer. (PubMed, Cancer Lett) - "Treatment with the OXPHOS inhibitor IACS-010759 suppressed the proliferation, migration, invasion, and metastasis of RNF43-mutant tumors. Our findings identify a RNF43-YBX1-MYC signaling axis associated with metabolic reprogramming in pancreatic cancer and suggest that OXPHOS inhibition may represent a potential therapeutic vulnerability in tumors with RNF43-inactivating mutations."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • IDH2 • IGF2BP1 • RNF43 • YBX1

Cyclin-dependent kinase-9 and oxidative phosphorylation inhibition overcome ibrutinib resistance in mantle cell lymphoma. (PubMed, Cancer Res Commun) - "OxPhos inhibitor IACS-010759 demonstrated synergy with AZD4573 in vitro. Thus, CDK9 inhibition exhibits activity in ibrutinib-resistant MCL and can be further enhanced by co-targeting of OxPhos."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDK9 • MCL1 • MYC

Modulating the tumor microenvironment (TME) to enhance anti tumor immunity using metabolic inhibitors (AACR 2026) - "Metabolic stress resulted in CAR-T cell dysfunction, while NCI-006 and IACS-010759 showed potential to improve the extracellular environment of the TME. Further studies are warranted to test the feasibility and efficacy of metabolic inhibitors in combination with CAR-T therapy."

Biomarker • IO biomarker • Tumor microenvironment • Neuroendocrine Tumor • Oncology • Solid Tumor • CD8 • LDHA • SSTR • SSTR2

MYC-driven Medulloblastoma is Sensitive to the Pyrimidine Synthesis Inhibitor H3B-120 (AAN 2026) - "For each line, mitochondria activity was assessed by live-cell staining for mitochondria with active potential and evaluated their sensitivity to inhibitors of nucleotide synthesis (Mizoribine, H3B-120, or 5-FU) in CyQuant Direct proliferation assays...While IACS-010759 increased lactic acid in both tumor and healthy cells, H3B-120 only increased lactic acid in the tumor lines. Conclusions Pyrimidine synthesis represents a key vulnerability for MYC-driven MB and offers a potential therapeutic alternative to Complex I inhibition with reduced systemic toxicity."

Brain Cancer • Medulloblastoma • Solid Tumor • MYC • MYCN

A novel therapeutic approach to overcome metabolic reprogramming in lung cancer (AACR 2026) - "Importantly, we utilized very low doses of the OXPHOS inhibitor IACS-10759 that are known to be well-tolerated in patients...Through quantitative proteomics, phospho-proteomics and kinase motif analysis, we identified several direct ROCK substrates including PPP1R12A and PPP1R12C that play critical roles in actin cytoskeleton regulation and glucose transport. Taken together, we identified the mechanistic underpinnings of a highly synergistic combination strategy that overcomes adaptive metabolic reprograming which has been a central challenge in the successful development of therapeutics targeting cancer metabolism."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ARID1A • SLC2A1 • SMARCA4

Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma (AACR 2024) - "As such, we aimed to understand the role of mitochondrial oxidative phosphorylation (OXPHOS) and redox homeostasis in ARID1A/B dual-deficient DDEC to create new treatment options. A panel of ARID1A/B dual-deficient and proficient endometrial cancer cell lines were treated with OXPHOS inhibitor IACS-010759 and reactive oxidative species (ROS)-inducing agent elesclomol to identify shifts in drug response between the two groups. ARID1A/B-dual deficient cancer cells rely on mitochondria function for survival. The underlying mechanisms are currently under investigation."

Endometrial Adenocarcinoma • Endometrial Cancer • Oncology • Solid Tumor • ARID1A • ARID1B

Mitochondrial complex I inhibition enhances chemotherapy efficacy in melanoma (AACR 2025) - "Previous efforts have focused on targeting glycolysis, while mitochondrial oxidative phosphorylation (OXPHOS) and TCA metabolism remain underexplored in melanoma research due to limited understanding of contexts in which OXPHOS is required for cancer cell growth and survival. To determine the impact of chemotherapies (Temozolomide and Cisplatin) on cellular metabolism, metabolomics profiling was performed using liquid chromatography-mass spectrometry (LC-MS) and bioenergetics analyses. Therapeutic responses were studied with chemotherapy in combination with a complex I inhibitor (Phenformin and IACS-010759)... These findings underscore the clinical promise of employing mitochondrial complex I inhibition as part of a combined therapeutic approach to enhance chemosensitivity for individuals with advanced and refractory melanoma."

Clinical • Melanoma • Oncology • Solid Tumor

Investigating metabolic sensitivity and organization of renal cell carcinoma: To enhance effective therapies and patient survival (AACR 2024) - "We have extended the analysis to RCC cell lines (786-O cell lines) and primary cells collected from nephrectomy specimens and matched metastatic biopsy samples, using current SOC pathway inhibitors (including sorafenib, sunitinib, belzutifan) and investigational metabolic drugs (metformin, IACS-010759, niclosamide).Results & Our preliminary results show an association of high OX-PHOS with primary tumors from early relapse after nephrectomy than the relapsed late tumors. Our preliminary results show an association of high OX-PHOS with primary tumors from early relapse after nephrectomy than the relapsed late tumors. Our biosensor single cell data show that even genetically homogeneous cell populations can vary in their usage of OXPHOS and glycolysis to supply ATP for cell growth. Tumor gene expression profile coupled with biosensor data, will address mechanism behind this metabolic shift in RCC tumors in primary cells isolated from primary and metastatic sites."

Clinical • IO biomarker • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • HIF1A • VHL

Therapeutic modulation of rock overcomes metabolic adaption to oxphos inhibition and suppresses tumor growth (AACR 2024) - "Steady-state metabolomics and C13-glucose isotope tracing confirmed downregulation of multiple glycolytic metabolites and reduced glycolytic flux by the combination of ROCK inhibition and IACS-10759 and was associated with severe reduction in glucose uptake. In summary, our study identified a key role of ROCK kinases in metabolic adaptation of cancer cells and provides a strong rationale for pursuing ROCK inhibitors as novel combination agents with OXPHOS inhibition and lay the foundation for future clinical investigation in genetically defined subtypes of lung cancer."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ARID1A • SMARCA4

Investigating the significance of OXPHOS activity in non-small cell lung cancer brain metastases (AACR 2024) - "The effects of the OXPHOS inhibitor IACS-010759 were assessed by cell growth as well as stable isotope tracing with [U-13C] glucose... OXPHOS activity may be enhanced in NSCLC brain metastases due to the unique metabolic environment of the brain. This elevated OXPHOS activity may be necessary for NSCLC brain metastasis growth, as OXPHOS inhibition reduced metastasis in the brain. NSCLC cells may undergo mitochondrial biogenesis to support survival in this unique metabolic environment, and this may represent an area of therapeutic vulnerability for brain metastases."

Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Metabolic dysregulations of aged bone marrow mesenchymal cells in Acute Myeloid Leukemia reveal novel therapeutic targets. (AACR 2025) - "Our results elucidate age-dependent metabolic dysregulations within the bone marrow microenvironment in AML and provide novel targetable approaches. Future portions of testing aim to identify the mechanism of action of AML-BMMSCs and OXPHOS."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • MYC

Chemokine-Like Receptor 1 Knockdown Suppresses Oral Squamous Cell Carcinoma Progression by Reducing Oxidative Phosphorylation. (PubMed, Int Dent J) - "CMKLR1 is a novel driver of OXPHOS in OSCC that functions through the PI3K/AKT/PGC-1α axis. Targeting mitochondrial metabolism may represent a promising therapeutic strategy for patients with overexpression of CMKLR1 and OSCC."

Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma

CRIP1 knockdown enhances glycolytic dependence and increases sensitivity to 2-Deoxy-D-Glucose in acute myeloid leukemia. (PubMed, Mol Biol Rep) - "Our findings indicate that CRIP1 knockdown induces a glycolytic switch in AML cells, rendering them exquisitely sensitive to glycolytic inhibition by 2-DG. This suggests that CRIP1 status could serve as a biomarker for predicting response to metabolic therapies and highlights 2-DG as a promising therapeutic agent for a subset of AML characterized by glycolytic dependency."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CRIP1 • LDHA

Advancing Precision Therapy in Pediatric Acute Myeloid Leukemia Through PDX Models and Mitochondrial Targeting. (PubMed, Blood Adv) - "Overall, our study highlights the power of AML-PDXs as a translational platform for novel targeted therapy identification. Our preclinical results testing Venetoclax+IACS-010759 in KMT2A-r AML strongly support mitochondrial targeting in this genetic AML subtype."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • KMT2A

OXPHOS inhibitor IACS010759 suppresses tumor growth by modulating autophagy in esophageal squamous cell carcinoma. (PubMed, Pathol Res Pract) - "The autophagy inducer rapamycin counteracted the inhibitory effects of IACS-010759, indicating that IACS-010759 inhibits ESCC autophagy via AKT/mTOR activation, thereby exerting anti-tumor effects. Combining IACS-010759 with the glycolysis inhibitor 2-DG resulted in a significant synergistic anti-tumor effect in ESCC cells and xenografts. In conclusion, our findings suggest that the OXPHOS pathway may serve as a promising therapeutic target for ESCC."

Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

F1 subunit-specific ATP synthase inhibition disrupts AML mitochondrial metabolism distinctly from other electron transport chain inhibitors (ASH 2025) - "In the PRISM drug repurposing dataset, we observedan inverse relationship between AML cell line sensitivity to IACS-010759 (inhibitor of complex I) andoligomycin (OGM, inhibitor of complex V) (Pearson -0.74, P = 0.0011)...NucleotideMS showed rapid interruption of nucleotide biosynthesis with all inhibitors by C13 incorporation butagain recapitulated the relative preservation of ADP/ATP ratio with EB2023 treatment alone – which wesuggest arises from EB2023 preventing the consumption of the existing ATP reservoir via compensatoryATP hydrolysis (reversal of ATP synthase).In summary, complex I inhibition leads to immediate interruption of cellular respiration, Fo inhibitionblocks protons from crossing the inner mitochondrial membrane and F1 inhibition decouples ATPproduction from respiration while still allowing protons to cross the inner mitochondrial membrane.EB2023 inhibits both ATP synthase and the reverse reaction of ATP hydrolysis directly at the catalytic..."

Acute Myelogenous Leukemia • Metabolic Disorders