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

Two-component system sensor kinase inhibitors target the ATP-lid of PmrB to disrupt colistin resistance in Acinetobacter baumannii | Poster Board #1126 (ACS-Fall 2026) - "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."

Targeted Protein Degradation

Two-component system sensor kinase inhibitors target the ATP-lid of PmrB to disrupt colistin resistance in Acinetobacter baumannii | Poster Board #1176 (ACS-Fall 2026) - "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."

Targeted Protein Degradation

Further optimization of the IMD-0354 scaffold generates potent colistin adjuvants with reduced eukaryotic toxicity that are active in vivo | Poster Board #1115 (ACS-Fall 2026) - "In a murine peritonitis model using a highly colistin-resistant K. pneumoniae strain, the combination of NDM-622 and colistin effected a decrease in colony forming units (CFUs) compared to treatment with either colistin alone or vehicle controls. Preliminary mechanism of action studies suggest that m-hydroxybenzanilides act via a mechanism distinct from the salicylanilides, evidenced by the absence of lipid A modification reversal, and no observable increase in reactive oxygen species generation, iron binding, or increased membrane permeability."

Preclinical • Infectious Disease • Pneumonia

IMD-0354 optimization generates potent colistin adjuvants with in vivo activity and reduced eukaryotic toxicity. (PubMed, Eur J Med Chem) - "In a murine peritonitis model using a highly a colistin-resistant K. pneumoniae strain, NDM-622 and colistin together effect a decrease in colony forming units (CFUs) compared to treatment with colistin alone or vehicle controls. Preliminary mechanism-of-action (MoA) studies suggest that m-hydroxybenzanilides, including NDM-622, likely act via a mechanism distinct from IMD-0354."

Journal • Preclinical • Infectious Disease • Pneumonia

Evaluation of mTOR, NFκB and BCL-2 Inhibitor Activity In Vitro in Karpas 1106P, a Primary Mediastinal B-Cell Lymphoma Cell Line. (PubMed, Hematol Rep) - "We administered three novel drugs: AZD2014 (vistusertib), an inhibitor of the serine-threonine kinase mTOR; IMD-0354, an NFκB inhibitor; and ABT-199 (venetoclax), a highly selective inhibitor for BCL-2. The combination of three drugs did not have a stronger effect than either a single drug used alone or any two-drug combination. These results provide preliminary in vitro evidence that targeting the BCL-2 and mTOR pathways may enhance pro-apoptotic activity in a PMBCL cell model; however, further validation in additional cell lines and in vivo models is needed before translational implications can be considered."

Journal • Preclinical • B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma

A Deep-Red-Absorbing Osmium(II)-Based Photosensitizer Evokes Pyroptosis by Targeting Glutamine Metabolism and Impairing Cell Redox Homeostasis. (PubMed, J Am Chem Soc) - "Specifically, an osmium-based photosensitizer (Os) was covalently attached to a small-molecule glutamine carrier protein inhibitor (IMD-0354), to construct the conjugate Os-IMD. As a result, upon light irradiation, Os-IMD induced mitochondrial damage and impaired electron transport chain function as well as intracellular redox homeostasis, leading to a switch in the mode of cell death from the apoptosis typically observed with Os to gasdermin D (GSDMD)-mediated pyroptosis. Our study offers a new avenue for the development of scalable pyroptosis-inducing agents."

Journal • Oncology

The Biocide Triclosan Drives the Inflammatory Responses in Epithelial Cells and Macrophages via ROS-Mediated Activation of ERK/NF-κB Signaling Pathways. (PubMed, J Appl Toxicol) - "Scavenging of TCS-induced ROS by N-acetylcysteine (NAC) could mitigate signaling pathways activation. As expected, inhibitors specific for ERK1/2 (PD98059) and NF-κB p65 (IMD0354) signaling pathways efficiently attenuated TCS-induced inflammatory response in BEAS-2B cells. Thus, ROS/ERK/NF-κB axis contributes to the TCS-induced inflammatory response. Further, animal studies are required for a better understanding of TCS-mediated inflammatory response in various organs, including the lungs."

Journal • Inflammation • Oncology

Jingxin Zhidong Formula Alleviates Tic Disorder via Modulation of Microglial IKK/NF-κB Signaling and Striatal Neurotransmitter Homeostasis. (PubMed, Brain Behav) - "JXZDF alleviated tic-like behaviors in a TD rat model by restoring striatal excitatory-inhibitory neurotransmitter balance and inhibiting microglial-mediated neuroinflammation. Its therapeutic effect was at least partially mediated by suppression of IKK/NF-κB. These findings provide a pharmacological basis for the clinical application of JXZDF in TD treatment."

Journal • Inflammation • Oncology • Tic Disorders • Tourette Syndrome • GRIA1 • IL6 • NFKBIA • TNFA

Evaluation of mTOR, NFκB, and BCL-2 Inhibitor Activity In Vitro on Diffuse Large B-Cell Lymphoma Cells. (PubMed, Curr Issues Mol Biol) - "Three novel drugs were administered: AZD2014 (vistusertib)-an inhibitor of the serine-threonine kinase mTOR; IMD-0354-an NFκB inhibitor; and ABT-199 (venetoclax)-a highly selective inhibitor for BCL-2. In pairs, the strongest effect was observed for AZD2014+ABT-199; furthermore, this effect was not intensified by the combination of the three drugs. Our findings, including those for the BCL-2 and mTOR inhibitors, indicate that there is a need for further in vivo studies to evaluate these drugs as potentially effective treatments for DLBCL of the ABC and GCB subtypes."

Journal • Preclinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Glutamine-Metabolism-Intervening Nanoplatform Activates Lipophagy to Potentiate Ferroptosis and Immune Activation in Breast Cancer. (PubMed, Adv Healthc Mater) - "As a proof-of-concept, we develop a nanoplatform for ferroptosis named MICLM, which is obtained by encapsulating chlorin e6 (Ce6, a photosensitizer) and IMD-0354 (an SLC1A5 inhibitor) into metal-organic framework (NH2-MIL-101(Fe)), followed by surface coating for tumor-targeting. Additionally, Gln metabolism inhibition attenuates immunosuppressive M2 macrophage polarization, ultimately boosting antitumor immunity. Thus, MICLM effectively induces ferroptosis and remodels the tumor immune microenvironment via amino acid metabolic intervention, offering a promising strategy for ferroptosis-based therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • SLC1A5

Myeloid Irf5 Deficiency Enhances the Therapeutic Efficacy of IMD-0354 in a TDP-25-Induced Neurodegeneration Model. (PubMed, Mol Neurobiol) - "Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Metabolic Disorders • Proteinopathy • IRF5 • TARDBP

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