IMD-0354 / Institute of Medicinal Molecular Design - LARVOL DELTA

A drug-repurposing screen of FDA- and EMA-approved drugs identifies two NF-κB inhibitors active against eumycetoma. (PubMed, J Antimicrob Chemother) - "NF-κB inhibitors bay117085 and IMD-0354 were able to prolong the survival of M. mycetomatis-infected larvae."

European regulatory • FDA event • Journal • Oncology

Regulation of inflammation by Chaihu-Shugan-San: Targeting the IL-17/ NF-κB pathway to combat breast cancer-related depression. (PubMed, Phytomedicine) - "This study systematically demonstrates that CSS ameliorates BCRD by suppressing the IL-17/ NF-κB pathway as well as modulating microglial polarization and elucidates the dual function of IL-17. These results point to a new multi-target intervention strategy for BCRD treatment and fully reflect the holistic effects of CSS by its multi-component as well as multi-target actions."

Journal • Breast Cancer • CNS Disorders • Depression • Mood Disorders • Oncology • Psychiatry • Solid Tumor • IL17A

Two-Component System Sensor Kinase Inhibitors Target the ATP-Lid of PmrB to Disrupt Colistin Resistance in Acinetobacter baumannii. (PubMed, Biochemistry) - "Subsequently, in vivo phosphorylation assays using this protein construct allowed for the evaluation of five compounds (IMD-0354, NDM-265, NDM-455, NDM-463, and NDM-497) that act as PmrBc inhibitors capable of preventing autophosphorylation and phosphotransfer independently. These compounds have been shown to eliminate colistin resistance in vivo. Finally, these results, paired with mass spectrometry and limited proteolysis investigations, enabled us to determine the mechanism of action of these compounds as well as their likely binding site on the ATP-lid of PmrB."

Journal • Targeted Protein Degradation

Arsenic-Induced Inflammatory Response via ROS-Dependent Activation of ERK/NF-kB Signaling Pathways: Protective Role of Natural Polyphenol Tannic Acid. (PubMed, J Appl Toxicol) - "As expected, the blockade of either ERK1/2 (PD98059) or NF-kB p65 (IMD0354), or both pathways attenuated As3+-induced pro-inflammatory mediators release. Interestingly, pre-treatment with ROS inhibitor N-acetylcysteine (NAC) attenuated activation of ERK/NF-kB pathways, suggesting that ROS have a critical role in pathway's activation and subsequent inflammatory response. Further, TA pre-treatment effectively attenuated As3+-induced inflammatory response by suppressing ROS production and ERK/NF-kB signaling pathways activation. Therefore, this study provides scientific evidence for the anti-inflammatory activities of TA and the underlying molecular mechanisms."

Journal • Inflammation • Oncology

Localized light-triggered release macrophage cytopharmaceuticals containing O-nitrobenzyl group for enhanced solid tumor cell-chemotherapy. (PubMed, Acta Pharm Sin B) - "Amphiphilic block copolymers with ultraviolet (UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors."

Journal • Tumor cell • Oncology • Solid Tumor

Exploring the impact of mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 on breast cancer cell metabolism. (PubMed, BMC Cancer) - "In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes."

Journal • Breast Cancer • Oncology • Solid Tumor • SLC2A1

Adjuvants restore colistin sensitivity in mouse models of highly colistin-resistant isolates, limiting bacterial proliferation and dissemination. (PubMed, Antimicrob Agents Chemother) - "Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii-induced peritonitis. These novel adjuvants show low toxicity in vivo, significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection."

Journal • Preclinical • Infectious Disease • Pneumonia

Halogenated Salicylanilide Derivatives of IMD-0354 Exhibit Dual-Action Antimicrobial/Colistin-Adjuvant Activity in Synthetic Sputum Co-Cultures of Pseudomonas aeruginosa and Staphylococcus aureus (ASM Microbe 2024) - "Genetic analyses of colistin-resistance genes in TRPA162 are currently underway. Mechanism of action and cell toxicity studies are planned for the near future.$$graphic_{7B133723-AB5D-4166-91A9-12A755F3DA69}$$"

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

Halogenated Salicylanilide Derivatives of IMD-0354 Exhibit Dual-Action Antimicrobial/Colistin-Adjuvant Activity in Synthetic Sputum Co-Cultures of Pseudomonas aeruginosa and Staphylococcus aureus (ASM Microbe 2024) - "Genetic analyses of colistin-resistance genes in TRPA162 are currently underway. Mechanism of action and cell toxicity studies are planned for the near future."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

Activation of ERK/NF-kB Pathways Contributes to the Inflammatory Response in Epithelial Cells and Macrophages Following Manganese Exposure. (PubMed, Biol Trace Elem Res) - "As expected, cells treated with inhibitors of ERK1/2 (PD98059) and NF-kB p65 (IMD0354) effectively mitigated the expression of various pro-inflammatory mediators induced by Mn2+, suggesting that ERK/NF-kB pathways have a critical role in the Mn2+-induced inflammatory response. Further, in vivo studies are required to confirm these in vitro findings to support clinical translation."

Journal • CNS Disorders • Inflammation • Oncology

In vitro primary hyperparathyroidism model application of computationally repurposed drugs. (PubMed, Mol Cell Endocrinol) - "Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion."

Journal • Preclinical • Endocrine Disorders • Oncology • Renal Disease

Promotion of Myofibroblast Differentiation Through Repeated Treatment of Fibroblasts to Low Concentrations of PM. (PubMed, Environ Toxicol Pharmacol) - "Treatment of fibroblasts with IMD0354, an inhibitor to nuclear factor κB, but not with an antagonist to aryl hydrocarbon receptor, abolished the ability of PM to induce myofibroblast differentiation. These data demonstrate that potential impact of PM to fibroblast activation and fibrosis and support the importance of utilizing low concentrations and varying exposure protocols to toxicologic studies."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Reducing the Invasiveness of Low- and High-Grade Endometrial Cancers in Both Primary Human Cancer Biopsies and Cell Lines by the Inhibition of Aquaporin-1 Channels. (PubMed, Cancers (Basel)) - "In contrast, proposed inhibitors of AQP water pores (acetazolamide, ginsenoside, KeenMind, TGN-020, IMD-0354) were not effective...In summary, AQP1 ion channels are important for motility in both low- and high-grade EC subtypes. Inhibition of AQP1 is a promising strategy to inhibit EC invasiveness and improve patient outcomes."

Biopsy • Journal • Preclinical • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • AQP1 • AQP8

Sodium Danshensu stabilizes atherosclerotic vulnerable plaques by targeting IKKβ mediated inflammation in macrophages. (PubMed, Biomed Pharmacother) - "SDSS stabilized vulnerable plaques and suppressed inflammatory responses by inhibiting the NF-κB pathway through its targeting of IKKβ."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Hematological Disorders • Inflammation • Thrombosis • APOE

Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats. (PubMed, Ann Transl Med) - "Our findings indicated that NF-κB activation is acritical step in the abnormal reactivity of glial cells in STZ-induced diabetic rats. Inhibition effect of IMD-0354 on NF-κB activation may represent a promising therapeutic strategy for DR via a variety of mechanisms, including inflammation reduction and glial cells regulation."

Journal • Preclinical • Diabetic Retinopathy • Inflammation • Retinal Disorders • NF-κβ

Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice. (PubMed, Pharmaceutics) - "Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses."

Journal • Preclinical • Hepatology • Immunology • Inflammation • NF-κβ

CC16 augmentation reduces exaggerated COPD-like disease in Cc16-deficient mice. (PubMed, JCI Insight) - "CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 protein solution (rhCC16) or a NF-kB inhibitor (IMD0354) versus vehicle beginning at the mid-point of the exposures. rhCC16 treatment reduced NF-kB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-kB activation and represents a novel therapeutic approach for COPD."

Journal • Preclinical • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants. (PubMed, iScience) - "IMD-0354 stimulated type I interferon antiviral response, inhibited viral entry, and down-regulated hijacked proteins. This study demonstrates that the conserved coronavirus signatures and the transcriptomic reversal approach that leverages polypharmacological effects could guide new variant therapeutic discovery."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis. (PubMed, Front Immunol) - "Besides, IMD 0354 and SP600125 addition attenuated MALT1's effect on Th2 and Th17 differentiation. MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in RA."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology • CD4 • MALT1

ACT001 suppressing M1 polarization against inflammation via NF-κB and STAT1 signaling pathways alleviates acute lung injury in mice. (PubMed, Int Immunopharmacol) - "Finally, we used IMD 0354 (IMD) and Fludarabine (Flud) to specifically block the activity of IKKβ and STAT1, and stimulated macrophages through IKKβ and STAT1 overexpression. Our data clearly showed that ACT001-induced decrease of the M1 polarization was blocked by IMD and Flud treatment, and reversed by IKKβ and STAT1 overexpression in RAW264.7 cells. In conclusion, we discovered that ACT001 significantly alleviates inflammation and limits M1 phenotype of pulmonary macrophages via suppressing NF-κB and STAT1 signaling pathways, providing new insights for the development of drugs to treat ALI/ARDS."

Journal • Preclinical • Acute Lung Injury • Fibrosis • Immunology • Inflammation • Oncology • Respiratory Diseases

Integrative Analysis for Identification of Therapeutic Targets and Prognostic Signatures in Non-Small Cell Lung Cancer. (PubMed, Bioinform Biol Insights) - "On the contrary, high mRNA expressions of CBL, FYN, LRKK2, and SOCS2 were associated with a significantly better prognosis. Furthermore, our drug target analysis for these hub genes suggests a potential use of Trichostatin A, Pracinostat, TGX-221, PHA-793887, AG-879, and IMD0354 antineoplastic agents to reverse the expression of these DEGs in NSCLC patients."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • CDC20 • CDK1 • CDKN2A • EZH2 • FYN • SOCS2

Lidocaine relieves murine allergic rhinitis by regulating the NF-κB and p38 MAPK pathways. (PubMed, Exp Ther Med) - "In order to further verify the association between the NF-κB and p38 MAPK signaling pathways and AR in mice, the effects of the NF-κB inhibitor IMD-0354 and the p38 MAPK inhibitor SB 203580 were assessed on AR mice. The results indicated that these two compounds exhibited similar inhibitory effects on AR mice as those noted with the use of lidocaine. These findings suggested that lidocaine represented a novel therapeutic agent for AR."

Journal • Preclinical • Allergic Rhinitis • Immunology • Inflammation • Mucositis • IFNG • IL13 • IL17A • IL2 • IL4 • IL5 • RELA • TNFA

Benzimidazole Isosteres of Salicylanilides are Highly Active Colistin Adjuvants (ACS-Sp 2022) - "Herein, we report the activity of a second-generation library of IMD-0354 analogues incorporating a benzimidazole moiety as an amide isostere. We identified several analogues that show increased colistin potentiation activity against the Gram-negative bacteria: Klebsiella pneumoniae and Acinetobacter baumannii."

Clinical • Infectious Disease • Pneumonia

Inhibition of macrophage migration inhibitory factor alleviates LPS-induced inflammation response of HEI-OC1 cells via suppressing NF-κB signaling. (PubMed, Cytokine) - "Inhibition of MIF alleviated LPS-induced inflammation in HEI-OC1 cells via inactivating the NF-κB signaling, which might provide a better understanding for SSNHL development."

Journal • Immunology • Inflammation • Otorhinolaryngology • MIF

Benzimidazole Isosteres of Salicylanilides Are Highly Active Colistin Adjuvants. (PubMed, ACS Infect Dis) - "Herein, we report the activity of a second-generation library of IMD-0354 analogues incorporating a benzimidazole moiety as an amide isostere. We identified several analogues that show increased colistin potentiation activity against Gram-negative bacteria."

Clinical • Journal • Infectious Disease • Pneumonia