echinomycin / Merck (MSD) - LARVOL DELTA

HIF-1α integrates lipogenic FASN and glycolytic GLUT3 to overcome intratumor oxidative and hypoxic stress for colorectal cancer metastasis. (PubMed, Oncogene) - "In vivo, lipid nanoparticle-encapsulated echinomycin rapidly suppressed HRE, SRE, and ARE activity, reduced peri-hypoxic induction of FASN and GLUT3, inhibited tumor growth, and eliminated lung metastasis. These findings define a growth factor-responsive, HIF-1α-centered stress-adaptive state and highlight HIF-1α transcriptional activity as a therapeutic target in metastatic CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • FASN • HIF1A • IGF1 • SLC2A3

Ref-1 drives ulcerative colitis induced systemic defects in hematopoietic cells. (PubMed, Commun Biol) - "Blockade of the redox-activity of APE1/Ref-1 with APX3330 inhibits the elevated expression of HIF-1α in HSPCs and reverses the aberrant HSPC dynamics under the inflammatory milieu of UC, including suppression of pro-inflammatory Ly6Chi monocytes. Using echinomycin, we pharmacologically blocked HIF-1α activity and found that HIF-1α mediates inflammatory responses via downstream IL-1r1 signaling. Blockade of the redox activity of ref-1 rescues the abnormal HSPC function. Our data highlight the significance of the APE1/Ref-1/HIF-1α/IL-1r1 signaling cascade in aberrant hematopoiesis that contributes to the pathophysiology of chronic UC through a feed-forward loop."

Journal • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • HIF1A • IL1R1

Myeloid HIF-1α Sustains Hypoxic Fibrotic Fronts and Drives Pulmonary Fibrosis. (PubMed, bioRxiv) - "In bleomycin-induced fibrosis, HIF-1α activity emerged first in macrophages and subsequently in fibroblasts within pimonidazole-marked hypoxic rims bordering nascent αSMA⁺ foci...Two lung-directed strategies, inhaled liposomal echinomycin and inhaled shHif1a lipid nanoparticles, phenocopied these effects, demonstrating therapeutic tractability. These findings define a hypoxic front-zone niche in which myeloid HIF-1α sustains macrophage persistence and promotes fibroblast activation and matrix remodeling. By linking spatial compartmentalization to causal genetics and lung-directed intervention, our work identifies myeloid HIF-1α as a mechanism-anchored, locally targetable driver of fibrotic lesion propagation."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Sarcoidosis • CD68 • HIF1A • PDGFRA

Echinomycin, a peptide antibiotic from a new bacterial source and its potential to tackle drug resistance in methicillin-resistant Staphylococcus aureus. (PubMed, Arch Microbiol) - "Furthermore, our findings indicate that piperine, when used as an adjuvant, modulates echinomycin activity by lowering its minimum inhibitory concentration (MIC) and potentially limiting the emergence of resistant MRSA mutants, thereby suggesting a reduced risk of AMR development. Overall, these in vitro findings provide a strong rationale for further validation using clinical strains of S. aureus, detailed dose-response analysis, and in vivo studies to enhance quantitative resolution and assess the therapeutic relevance in clinical settings."

Journal • Infectious Disease

Intracellular C. neoformans infection stimulates increased glycolytic activity in fetal liver-derived alveolar-like macrophages. (PubMed, bioRxiv) - "Furthermore, activation or inhibition of hypoxia inducible factor 1 (HIF1) activity utilizing dimethyloxalylglycine (DMOG) and echinomycin, respectively, indicates that the expression of select glycolytic genes in C. neoformans -infected FLAMs is HIF1-dependent. Collectively, our results suggest that FLAMs serve as an appropriate tool for modeling AM: C. neoformans interactions and investigating the effects of this pathogen on host AM immunometabolism."

Journal • Dermatology • Infectious Disease • HIF1A • IFNG • LDHA • PGK1 • SLC2A1

RETRACTED: Thomas et al. Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo. Cancers 2020, 12, 2279. (PubMed, Cancers (Basel)) - "The journal retracts the article, "Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo" [...]."

Journal • Preclinical • Oncology • Pancreatic Cancer • Solid Tumor

Antibody drug conjugates of echinomycin-based payloads. (PubMed, Bioorg Med Chem) - "The research resulted in potent quinoline/quinoxaline-based payloads that were further elaborated with linkers for conjugating to antibodies. Targeting and non-targeting ADCs yielded potent and selective conjugates."

Journal • HER-2

A New Furan-Type Secondary Metabolite Produced by the Echinomycin-Producing Marine Actinomycete Streptomyces sp. KM14-19. (PubMed, Chem Pharm Bull (Tokyo)) - "KM14-19. The structure of 1 was elucidated by an analysis of spectroscopic data, including 1 dimensional (1D) and 2D-NMR and single-crystal X-ray diffraction."

Journal

HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4. (PubMed, J Pharmacol Sci) - "In this study, we investigated whether echinomycin, a HIF-1α inhibitor, reduced the expression of proteins of aerobic glycolysis, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), and whether HIF-1α stabilization is involved in osteoclast differentiation...It also inhibited osteoclast differentiation and suppressed osteoclast bone-resorbing activity. We propose that HIF-1α inhibition suppresses excessive osteoclast differentiation and may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis."

Journal • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • HIF1A • LDHA • SLC2A1

Inhibiting Hypoxic Macrophages for Effective Pulmonary Fibrosis Intervention (ATS 2025) - "Using a bleomycin-induced PF mouse model, we further investigated the role of HIF1α in macrophage-driven fibrosis by employing LysM-Cre HIF1α conditional knockout mice to selectively deactivate HIF1α in myeloid cells. Additionally, liposome-encapsulated echinomycin (LEM) was administered as a pharmacologic HIF1α inhibitor targeting hypoxic macrophages...This macrophage-focused intervention significantly reduces ECM deposition and fibrotic progression, suggesting that HIF1α inhibition in macrophages could be a promising treatment approach to mitigate or even reverse PF. The efficacy of LEM underscores the potential of this pathway for developing targeted antifibrotic therapies."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • HIF1A • IL6 • TNFA

IL-9 promotes migratory dissemination of malignant T-cells by activating the HIF-1α-Cofilin-1 axis in cutaneous T-cell lymphoma. (PubMed, Mol Cancer Res) - "Finally, pharmacological antagonism of HIF-1α activity using the FDA-designated orphan drug, echinomycin, significantly abrogated IL-9-triggered migration of both malignant T-cell lines as well as patient-derived T-cell lymphoma cells from CTCL biospecimens. Implications: Our results uncover a CTCL-intrinsic IL-9-HIF-1α-Cofilin-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and Cofilin-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination."

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • HIF1A • IL9

Hypoxia-inducible factor-targeting therapy augmented the sensitivity to programmed death ligand-1 blockade by enhancing interferon-γ-induced chemokines in tumor cells. (PubMed, Int J Cancer) - "We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro...Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11."

IO biomarker • Journal • Tumor cell • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • CD8 • CXCL10 • HIF1A • IFNG • PD-L1

EmbB and EmbC regulate the sensitivity of Mycobacterium abscessus to echinomycin. (PubMed, mLife) - "In summary, our study demonstrates that ECH exerts potent anti-Mab activity and confirms that EmbB and EmbC are implicated in Mab's sensitivity to ECH. Mutation in EmbB may partially compensate for a loss of EmbC function."

Journal • Immunology • Infectious Disease

Structural basis of water-mediated cis Watson-Crick/Hoogsteen base-pair formation in non-CpG methylation. (PubMed, Nucleic Acids Res) - "DNA duplexes complexed with the DNA binding drug echinomycin result in increased occupancy of the (w)cWH geometry in the methylated base-pair (from 0.1 to 0.3)...This particular geometry is specific to non-CpG methylated dinucleotide sites in B-form DNA. Overall, the current study provides new insights into DNA conformation during epigenetic regulation."

Journal • Oncology

The role of Sirtuin 1 in regulation of fibrotic genes expression in pre-adipocytes. (PubMed, J Diabetes Metab Disord) - "Involvement of Hif-1α was evaluated by treatment with echinomycin...Activation of Sirt1, similar to suppressing of Hif-1α in pre-adipocytes may be a beneficial approach for attenuating fibrotic gene expression. The online version contains supplementary material available at 10.1007/s40200-024-01389-4."

Journal • Fibrosis • Immunology • HIF1A • LOX • MMP2 • MMP9 • SIRT1 • SPP1

Quinomycins with an unusual N-methyl-3-methylsulfinyl-alanine residue from a Streptomyces sp. (PubMed, J Antibiot (Tokyo)) - "Four new echinomycin congeners, quinomycins M-P (1-4) were isolated from the cultures of the soil-derived Streptomyces sp...Compounds 1-4 represent the first examples of quinomycin-type natural products with the sulfur atom at the N,S-dimethylcysteine residue oxidized as a sulfoxide group forming the unusual N-methyl-3-methylsulfinyl-alanine residue. Bioassay results revealed that the oxidation of the sulfur atom at the Cys or Cys' residues led to dramatic decrease of cytotoxicity and antimicrobial activity."

Journal

Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition. (PubMed, Mar Drugs) - "However, despite the massive increase in the number of marine natural products classified as 'anticancer leads,' most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy."

Journal • Review • Oncology • Solid Tumor • HIF1A

Cadmium contributes to cardiac metabolic disruption by activating endothelial HIF1A-GLUT1 axis. (PubMed, Cell Signal) - "Administration of HIF1A small molecule inhibitor echinomycin and A-485 reversed CdCl2-mediated increase of glucose uptake in endothelial cells...Our study uncovered the molecular mechanisms of Cd in contributing cardiac metabolic disruption by inhibiting HIF1A degradation and increasing GLUT1 transcriptional expression. Inhibition of HIF1A could be a potential strategy to ameliorate Cd-mediated cardiac metabolic disorders and Cd-related cardiovascular diseases."

Journal • Cardiovascular • Metabolic Disorders • Targeted Protein Degradation • HIF1A • SLC2A1

Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent. (PubMed, Sci Rep) - "Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HIF1A

Assessment of a Syndecan-1 targeted theranostic nanoparticle for improved detection and treatment of pancreatic cancer (RSNA 2023) - "Syndecan-1 targeted nanodelivered echinomycin resulted in significant survival increases compared to gemcitabine (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant tumors. Collectively, these findings support syndecan-1-targeted delivery of echinomycin and dysregulation of autophagy to induce cell death in pancreatic cancer. *Clinical Relevance/Application: Neither improved detection or neoadjuvant treatment of pancreatic cancer have substantially changed in decades."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • IGF1 • SDC1

Tumor cell autonomous innate immune signaling drives therapeutic resistance in head and neck tumors (SITC 2023) - "Echinomycin, a HIF1α inhibitor, significantly impaired the growth of MOC2 tumors (figure 3C,D)...Conclusions This study establishes a basis for self-propagating inflammatory signaling in HNC tumors driven by HIF1α, IL-1α and STAT3. Disruption of this loop by targeting the IL-1α or HIF1A signaling pathways represent promising strategies to overcome therapeutic resistance and induce anti-tumor immunity."

IO biomarker • Tumor cell • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CXCL8 • EPAS1 • HIF1A • IL1R1 • IL6 • TLR2 • TLR4

Exploring the Role of Drug Repurposing in Bridging the Hypoxia-Depression Connection. (PubMed, Membranes (Basel)) - "By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • HIF1A

HIF-1 Inhibition Reduces Venous Thrombosis in a Murine Polycythemia Vera Model (ISTH 2023) - "VF mice have increased expression of HIF-1 mediated genes as compared to WT (Figure 1). Echinomycin treatment reduced HIF-1 mediated gene expression without affecting peripheral blood cell counts (Figure 1). VF mice had significantly larger venous thrombi than WT littermates (Figure 2)."

Preclinical • Cardiovascular • Hematological Disorders • Polycythemia Vera • Thrombosis • Venous Thromboembolism • HIF1A

ApoE4-related microvascular disease in the Alzheimer's disease hippocampal CA1 stratum radiatum. (PubMed, Neuroscience) - "The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease."

Journal • Alzheimer's Disease • CNS Disorders • Vascular Neurology • APOE • CASP3 • HIF1A • KDR • SOD2

IL-9 driven pseudohypoxia promotes metastasis in Cutaneous T-cell lymphoma (CTCL) through the HIF-1α/Cofilin-1 axis (EACR 2023) - "Finally, there was overexpression of HIF-1α and Cofilin-1 in CTCL skin biopsies, underscoring the importance of this axis as a clinically relevant therapeutic target in CTCL.ConclusionThrough this study, we identified and validated the critical association of the IL-9/HIF-1α/Cofilin-1 axis in CTCL tumor metastasis. Our data thus supports echinomycin-based targeting of HIF-1α as a potential anti-metastatic therapy in T-cell malignancies."

Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • HIF1A • IL9