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

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

LSD1 inhibition enhances venetoclax efficacy in Acute Myeloid Leukemia via metabolic rewiring (ASH 2025) - "Supporting this, combiningbomedemstat with OxPhos inhibitors (IACS-010759, rotenone, antimycin, oligomycin) synergisticallyreduced cell proliferation, and Rho-zero MOLM-13 cells, lacking mitochondrial DNA, were more sensitiveto bomedemstat than wild-type cells.Consistent with its metabolic effects, bomedemstat increased expression (P = 0.0002) and activation (P =0.02) of the energy stress sensor AMPK, as shown by western blotting. Bomedemstat and venetoclax co-treatment showed synergistic anti-leukemic effects in AMLmodels in vitro and in vivo. Our findings suggest that LSD1 inhibition primes AML cells to venetoclax viadifferentiation-induced metabolic rewiring and activation of AMPK-mediated stress responses, providingthe basis for a planned clinical trial."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • DNMT3A • FLT3 • HOXA9 • IDH2 • MEIS1 • NPM1 • PTPRC • WT1

Novel Promising Therapeutic Strategies for Advancing the Treatment of KMT2A-Rearranged AML (ASH 2024) - "We selected Asparaginase (ASPN), IACS-010759 (IACS), Disulfiram, Gallein, 5-Azacytidine, Quizartinib, Trametinib, γ-Secretase inhibitor and ICG-001 to be tested either alone or in combination with Venetoclax (VEN) in 3D with ex vivo AML cells and AML patient derived MSCs. We support the use of pediatric AML-PDXs in preclinical testing for their ability to mimic the heterogeneity of drug response, aiding in the identification of tailored second-line treatments. VEN+ASPN combination represents a novel promising therapeutic strategy for advancing the treatment of KMT2A-rearranged AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CREBBP • CTNNB1 • FAT1 • FLT3 • KDM5A • KMT2A • NOTCH1 • NRAS • TET2

Mitochondrial complex I inhibitor, IACS synergistically enhances the radio-therapeutic effect for the intracranial S180 sarcoma mouse model (SNO 2025) - "This study investigates how mitochondrial complex I (CI) inhibition by IACS-010759 (IACS) sensitizes tumor cells to RT, focusing on metabolic disruption, DNA damage response, and survival.Methods The synergy between IACS and RT was assessed in S-180 sarcoma cells with four groups: control, IACS, RT, and RT + IACS...MRI indicated the greatest tumor reduction and improved survival in the RT + IACS group.Conclusion The combination of RT with metabolic inhibition effectively disrupts metabolic flexibility in S180 sarcoma, leading to ROS accumulation, impaired DNA repair, enhanced apoptosis, and reduced tumor stemness. Targeting tumor cell metabolism represents a promising strategy for enhancing RT efficacy by overcoming multiple resistance mechanisms."

IO biomarker • Preclinical • Metabolic Disorders • Sarcoma • Solid Tumor • BAX • BCL2 • CASP3 • CDKN1A • SOD2 • TP53

A TROP2-targeting ADC synergizes with oxidative phosphorylation inhibitor to enhance apoptosis in ESCC by suppressing the PI3K-AKT-mTOR signaling pathway. (PubMed, Cell Death Dis) - "Here, we investigated the therapeutic efficacy of IMMU132 (IMMU), an ADC targeting TROP2, either alone or in combination with IACS010759 (IACS), a selective OXPHOS inhibitor, through clinically ESCC models. Moreover, the data confirmed that inhibition of the PI3K-AKT-mTOR pathway significantly suppressed ESCC tumor growth following administration of the combination therapy. Based on these findings, we present a novel therapeutic strategy that enhances the efficacy of TROP2-targeting ADCs via concurrent inhibition of OXPHOS, which is likely to improve clinical outcomes of patients with TROP2-positive ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma

CDK9 Inhibition Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma (MCL) (ASH 2023) - "IACS-010759, an inhibitor of complex I of the ETC which targets OxPhos, demonstrated synergy with AZD4573 in parental and ibr-resistant MCL cell lines. CDK9 inhibition with AZD4573 induced apoptosis, downregulated MYC and MCL1 and NFκB signaling, and overcame ibr resistance in preclinical MCL models. This was also noted in a sample obtained from a clinical trial. Prolonged CDK9 inhibition led to metabolic reprogramming towards OxPhos, which thus can serve as a therapeutic target in MCL."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CD40LG • CD5 • MYC • PTPRC • TGFB1 • TNFA

Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis. (PubMed, JCI Insight) - "We developed multiple MRD models both in vitro (rapamycin persistent, RP) and in vivo after mTORC1 inhibition. MYC and SWI/SNF expression was significantly enhanced. Both the SWI/SNF inhibitor AU-15330 and the mitochondrial complex I oxidative phosphorylation inhibitor IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance."

Journal • Oncology • MYC

Mitochondrial complex I inhibitor, IACS synergistically enhances the radio-therapeutic effect for the intracranial S180 sarcoma mouse model (WFNOS 2025) - "This study investigates how mitochondrial complex I (CI) inhibition by IACS-010759 (IACS) sensitizes tumor cells to RT, focusing on metabolic disruption, DNA damage response, and survival.Methods The synergy between IACS and RT was assessed in S-180 sarcoma cells with four groups: control, IACS, RT, and RT + IACS...MRI indicated the greatest tumor reduction and improved survival in the RT + IACS group.Conclusion The combination of RT with metabolic inhibition effectively disrupts metabolic flexibility in S180 sarcoma, leading to ROS accumulation, impaired DNA repair, enhanced apoptosis, and reduced tumor stemness. Targeting tumor cell metabolism represents a promising strategy for enhancing RT efficacy by overcoming multiple resistance mechanisms."

IO biomarker • Preclinical • Metabolic Disorders • Sarcoma • Solid Tumor • BAX • BCL2 • CASP3 • CDKN1A • SOD2 • TP53

Minimal Residual Disease in Acute Myeloid Leukemia Following Induction Chemotherapy Can be Effectively Eradicated By Targeting Mitochondrial Metabolism (ASH 2023) - "Acute myeloid leukemia (AML) stem cells (AMLSCs) AMLSCs and residual cytarabine (AraC)-resistant AML cells (constituting minimal residual disease, MRD) thought to be responsible for chemoresistance and treatment failure, were shown to be highly dependent on mitochondrial function for survival and thus are vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS) (Farge et al...Here we evaluated OXPHOS dependency of AML MRD cells and determined impact of OXPHOS blockade on residual AML cells surviving standard chemotherapy (Doxorubicin/AraC, DA)...Next, the efficacy of IACS-010759 together with DA chemotherapy was evaluated in several chemotherapy-sensitive and -resistant animal models in vivo...Nat Med 2023) showed toxicities impeding its clinical utility, our data advocate for combining mitochondrial targeting strategies with chemotherapy as a part of induction and consolidation treatment for improved control of MRD, eradication of AMLSC and..."

Minimal residual disease • Residual disease • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • IL3RA • TP53

The Role and Mechanism of NDUFS2 in FLT3-Mutated Acute Myeloid Leukemia (ASH 2024) - "Additionally, the inhibition of mitochondrial complex I by the inhibitor IACS-010759 can synergize with Gilteritinib to combat FLT3-mutated AML. This indicates that NDUFS2 may serve as a potential target for the treatment of FLT3-mutated AML and enhance the sensitivity of targeted drugs to FLT3-mutated AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Pursuing Leukemia Stem Cells Definition in Pediatric Acute Myeloid Leukemia (ASH 2024) - "Additionally, a 72-hour treatment with the chemotherapy agent cytarabine in 3D showed that RL cells were insensitive to this treatment, supporting the RL fraction being chemo-resistant...This result was corroborated by treating 3D scaffolds seeded with RL or RH cells with the complex I inhibitor IACS-010759, which was only effective in reducing RL viability (p<0.05)...This novel strategy of RL cell recognition allows to identify a LSCs population that needs to be targeted to reduce relapse events. Novel mitochondrial vulnerabilities and nutrient dependences are under evaluation to improve AML eradication."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD34 • CD38 • FLT3 • KMT2A • NUP98

Amphiregulin and Epiregulin Confer Radioresistance in Esophageal Squamous Cell Carcinoma Through Oxidative Phosphorylation. (PubMed, Adv Sci (Weinh)) - "Functional experiments demonstrated that radioresistant ESCC cells (KYSE410R) exhibited elevated OXPHOS activity, which is reversed by targeting TCA cycle enzymes (CPI-613 (Devimistat), fumarate hydratase-IN-1 (FH-IN-1), etc.) or Oxidative phosphorylation (OXPHOS) inhibitors (IACS-010759, Rotenone, etc.). Clinically, high Amphiregulin/Epiregulin (AREG/EREG) levels correlated with nCRT resistance and poor prognosis. Collectively, the CEBPB/AREG/EREG axis drives radioresistance by reprogramming OXPHOS, suggesting inhibition of this pathway or OXPHOS itself as a promising strategy to enhance ESCC therapeutic responses."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • AREG • CEBPB • EREG • FH

AN INTEGRATED MULTI-OMICS ANALYSIS PREDICTS NEOADJUVANT CHEMOTHERAPY RESPONSE IN ADVANCED OVARIAN CANCER (IGCS 2025) - "Introduction: Neoadjuvant chemotherapy (NACT) is one of standard therapeutic paradigm in high-grade serous ovarian carcinoma (HGSOC), but lack of efficient biomarker to predict the response before therapeutic decision-making. 102 pre- and post- NACT tumor samples were subjected to genomics and RNA sequencing, including 13 paired specimens performed proteomics and metabolomics additionally. NACT induced significant immune remodeling, characterized by enhanced infiltration of B cells and NK cells, alongside activation of BCR /TCR, antigen presentation signaling pathways, while suppressing mitochondrial energy metabolism. Notably, nab-paclitaxel outperformed conventional paclitaxel in activating B cell-mediated humoral immunity. Transcriptomic stratification delineated:CRS-high tumors exhibited immune-active phenotypes, marked by B cell infiltration and complement cascade activation, validated by mIHC and proteomic,CRS-low tumors displayed OXPHOS hyperactivity, with..."

Clinical • Metastases • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

The integration of single-cell and metabolomics reveals the increase of oxidative phosphorylation during the liver metastasis of colorectal cancer. (PubMed, Cancer Metab) - "This study identifies OXPHOS upregulation as a key metabolic alteration during CRC liver metastasis, which could be induced by TGFβ signaling pathway. These findings contribute to a refined understanding of CRC metabolic adaptation in liver metastases and may inform therapeutic strategies targeting OXPHOS in advanced CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor

ACTL6A regulates the Warburg effect through coordinated activation of AP-1 signaling in head and neck squamous cell carcinoma. (PubMed, bioRxiv) - "They also sensitize treatment resistant HNSCC cells to the tumor killing effects of the complex I inhibitor IACS-010759 in vivo...Our results link SWI/SNF subunit amplification with potentiation of MAPK signaling in HNSCC and provide a novel mechanism by which cancer cells drive aerobic glycolysis and reduce mitochondrial dependency. We leverage these findings to propose treatment strategies for hypoxic tumors with SWI/SNF subunit amplifications."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EPAS1 • HIF1A • LGALS1

Targeting bone marrow mesenchymal stromal cells-derived IL-6 to overcome acute myeloid leukemia chemoresistance. (PubMed, Blood Adv) - P | "Importantly, Il6 deletion in MSCs reduced oxidative phosphorylation (OXPHOS) activity in AML cells, slowed disease progression, and enhanced the chemosensitivity to cytarabine (Ara-C). Similarly, the OXPHOS inhibitor IACS-010759 improved chemosensitivity in AML mice...Targeting IL-6 in MSCs may offer a promising therapeutic strategy for AML. NCT06486350."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IL6 • PRRX1

Synthesis and evaluation of new 5-(1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole derivatives and their application as OXPHOS inhibitors. (PubMed, Eur J Med Chem) - "In PC9 xenograft nude mice, TGI of 28c is 74.4 % compared with 44.16 % of the reference IACS-010759 when oral administration at dosage of 7.5 mg/kg. Mechanism research showed that 28c can bind with respiratory chain complex I, modulate the levels of NADH, NAD+ et al. in PC9 cells, activate cellular ROS and down regulate NRF2 and cause DNA damage in tumor cells."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies. (PubMed, Cancer) - "This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF

DISRUPTING MITOCHONDRIAL FUNCTION IN ACUTE MYELOID LEUKEMIA: PERSONALIZED APPROACH TO THERAPEUTIC STRATEGY COMBINING BCL-2 INHIBITION WITH COMPLEX I BLOCKADE (EHA 2025) - "Venetoclax (VEN) induces apoptosis by inhibiting BCL-2, and regulates ATP flux through the voltage-dependent anion channel (VDAC)...In vivo efficacy studies in 10 PDX AML models evaluated anti-leukemic potential upon mono- and combinatorial therapies.IACS-010759 inhibited growth, reduced viability and ATP production in 10 of 25 AML cell lines, and 67% of examined primary blasts and CD34+ cells, but was sparing hBM cells... This study supports targeting OxPhos as a promising strategy for AML. IACS, a potent compound for targeting mitochondria, induces energy depletion, inhibits proliferation, and promotes differentiation, particularly in FLT3 and IDH1/2-mutated AMLs with low SRC. Inhibiting BCL-2 with VEN reduces oxygen consumption and increases reactive oxygen species (ROS), enhancing the combined anti-leukemic efficacy in vitro and in vivo."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • BCL2 • CD34 • FLT3 • IDH1 • IDH2 • NPM1 • TP53

MUSASHI-2 PROMOTES CHEMOTHERAPY RESISTANCE OF INFANT KMT2A-REARRANGED ACUTE LYMPHOBLASTIC LEUKEMIA VIA REGULATING THE BIOENERGETIC METABOLISM. (EHA 2025) - "We demonstrated that Metformin and Tigecycline treatment in combination with GCs have synergistic effects in vitro. Overall, our study unraveled a novel potential role of MSI2 in regulating the energy metabolism of KMT2Ar ALL cells upon Glucocorticoid treatment and Glycolysis inhibition, thus suggesting that MSI2 might be involved in metabolic rewiring of leukemic cells under stress condition. Finally, our study paves the way for targeting the mitochondrial metabolic vulnerabilities of leukemia to improve treatment response in infants with KMT2Ar B-ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • AFF1 • CNTRL • KMT2A • MSI2

IMPACT OF MITOCHONDRIAL DNA MUTATIONS ON METABOLIC ADAPTATION AND TYROSINE KINASE INHIBITOR RESPONSE IN CHRONIC MYELOID LEUKAEMIA (EHA 2025) - "This effect was further enhanced by the combination of IACS-10759 and 2 µM imatinib (p<0.0001; Figure 1C), while normal CD34⁺ cells remained unaffected. At diagnosis, CP-CML cells with a high mtDNA mutation burden exhibit reduced mitochondrial respiration and increased sensitivity to TKIs, whereas cells with a low mtDNA mutation burden display enhanced oxidative metabolism and TKI resistance. Targeting mitochondrial metabolism may therefore provide a novel strategy to overcome TKI resistance in CML."

Tumor mutational burden • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • CD34 • TMB

Targeting mitochondrial complex I of CD177+ neutrophils alleviates lung ischemia-reperfusion injury. (PubMed, Cell Rep Med) - "Targeting mitochondrial function with the complex I inhibitor IACS-010759 reduces CD177+ neutrophil activation and alleviates lung injury in both mouse IRI and rat left lung transplant models. These findings provide a comprehensive landscape of CD177+ neutrophil-driven inflammation in lung IRI and highlight its potential value for future early diagnosis and therapeutic interventions."

Journal • Cardiovascular • Inflammation • Reperfusion Injury • Respiratory Diseases • Transplantation • CD177

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

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

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis. (PubMed, Nature) - "In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML."

Journal • Acute Myelogenous Leukemia • Diabetes • Hematological Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • Transplantation • DNMT3A • NDUFB1