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

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

Targeting Mitochondrial Complex I of Cd177+ Neutrophils Alleviates Lung Ischemia-Reperfusion Injury (ISHLT 2025) - "Moreover, the downregulation of CD177 impairs mitochondrial complex I assembly and compromises oxidative phosphorylation in neutrophils. Notably, inhibiting the complex I with IACS-010759 markedly relieves lung injury in a rat model of orthotopic left lung transplantation.Conclusion The study concludes that CD177+ neutrophils not only underline a crucial mechanism in PGD but also promise a new direction for biomarker and therapeutic target."

Cardiovascular • Inflammation • Reperfusion Injury • Respiratory Diseases • CD177

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer. (PubMed, Cell Death Dis) - "The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment."

Journal • Oncology • AIFM2 • GPX4

A m6A-Altering Variant of MRPL34 Predisposes to Hepatocellular Carcinoma via Regulating Oxidative Phosphorylation (APASL 2025) - "Moreover, the anticancer effects of oxidative phosphorylation (OXPHOS) inhibitor IACS-010759 with Cabozantinib or Lenvatinib were analyzed in cell, animal, and organoid models... The rs6903-m6A-MRPL34-OXPHOS axis provides a new perspective for understanding HCC risk and progression, as well as novel intervention strategies for HCC therapy. Table and Figure:Figure 1.A proposed model for the functional mechanism of the HCC risk-associated variant rs6903 altering m6A modification of MRPL34"

Hepatocellular Cancer • Oncology • Solid Tumor • METTL14 • METTL3 • WTAP • YTHDF2

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy. (PubMed, Clin Cancer Res) - "Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics."

Journal • Oncology • Solid Tumor

SMARCA4/BRG1 deficiency induces a targetable dependence on oxidative phosphorylation in clear cell renal cell carcinoma. (PubMed, Carcinogenesis) - "The efficacy of IACS-010759 stems from its ability to induce energy deprivation, pinpointing OXPHOS inhibition as a promising therapeutic approach for targeting SMARCA4-mutant tumors. This strategy offers a novel avenue to address a currently unmet therapeutic need, highlighting the potential of OXPHOS inhibition in the treatment of cancers harboring SMARCA4 mutations."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • SMARCA4

DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma. (PubMed, Dev Cell) - "Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • SLC1A5 • SMAD3 • TGFB1

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

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

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 Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3

Mechanisms of Mitochondrial Complex-I sensitivity in GBM (SNO 2024) - P2 | "The mechanisms of action of metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that its therapeutic effects in tumor cell growth and signaling are dependent on inhibition of mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of mitochondrial complex I inhibitors (MCI-i) such as IM156, IACS-010759, are currently under investigation. We are performing joint pathway analysis by examining differentially expressed genes and stable isotope tracing studies to determine distinct metabolic signatures in the two subsets of GBM. We are also performing Classification And Regression Tree (CART) analysis on a cohort of sixty primary GBM lines and tissues to predict if PDHA expression provides a binary outcome for MCI-i sensitivity."

Diabetes • Glioblastoma • Metabolic Disorders • Type 2 Diabetes Mellitus • SLC22A1

Inhibition of OXPHOS induces metabolic rewiring and reduces hypoxia in murine tumor models. (PubMed, Clin Transl Radiat Oncol) - "The metabolic effects of three OXPHOS inhibitors IACS-010759, atovaquone and metformin were explored by measuring oxygen consumption rate, extra cellular acidification rate, and [18F]FDG uptake in 2D and 3D cell culture. Reduced hypoxia by OXPHOS inhibition might enhance therapy efficacy in future studies. However, caution is warranted as systemic metabolic rewiring can cause adverse effects."

Journal • Preclinical • Oncology • Solid Tumor

Inhibition of OXPHOS reduces tumor hypoxia and induces metabolic rewiring as measured by [18F]FDG (EANM 2024) - "By the inhibition of OXPHOS, using mitochondrial inhibitor IACS-010759, we hypothesize that the oxygen demand of the tumor can be decreased... We showed that inhibition of OXPHOS can reduce hypoxia in spheroids and tumors, potentially increasing radio and immunotherapy efficacy. Furthermore, we show tumor cells are metabolically plastic and switch their metabolism from OXPHOS to glycolysis when OXPHOS is pharmacologically inhibited, resulting in increased glucose uptake in tumor cell spheroids. In vivo we observed increased serum lactate levels and increased [18F] FDG uptake in several healthy tissues, but not in the tumor."

Oncology • Solid Tumor

Mitochondrial Elongation and ROS-Mediated Apoptosis in Prostate Cancer Cells under Therapy with Apalutamide and Complex I Inhibitor. (PubMed, Int J Mol Sci) - "In this study, we investigated the effects of the androgen receptor antagonist apalutamide (ARN) and the mitochondrial electron transport chain complex I inhibitor IACS-010759 (IACS) on the mitochondrial network architecture and dynamics in PCa cells. Notably, the combination treatment with ARN and IACS resulted in increased apoptotic cell death and mitochondrial oxidative stress selectively in the androgen-sensitive PCa cells. Our findings highlight the therapeutic potential of targeting mitochondrial metabolism in prostate cancer and emphasize the need for further mechanistic understanding to optimize treatment strategies and improve patient outcomes."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Exploiting synthetic-lethal interactions for therapeutic development against aggressive MYC-driven tumors (EACR 2024) - "In preclinical models, tigecycline and IACS-010759 independently synergized with the BCL2 inhibitor venetoclax (ABT-199) against double-hit lymphoma (DHL), a high-grade form of B-cell lymphoma with concurrent activation of the MYC and BCL2oncogenes [2, 3]. 5). Our current research aims to unravel the mechanistic basis of this dual effect and to understand how it might be further exploited toward therapeutic development."

Synthetic lethality • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC

Exploiting metabolic adaptations in mitochondrial reprogramming of prostate cancer (EACR 2024) - "Similarly, mitochondrial ROS was strongly upregulated in androgen-sensitive cell lines.Conclusion Our study reveals that targeting mitochondrial dynamics through a combination of IACS-010759 and apalutamide induces mitochondrial elongation, enhances oxidative stress and cell death specifically in androgen-sensitive prostate cancer cells. This approach shows promise in overcoming drug resistance and improving treatment outcomes in prostate cancer."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • AR