M5*
Development of Gasdermin D Inhibitors for the Treatment of Stroke and Reperfusion Injury with an upside in ANCA and Autoimmune Diseases
Prof. Arturo Zychlinsky, Max Planck Institute for Infection Biology; Prof. Herbert Waldmann, Max Planck Institute of Molecular Physiology; Prof. Matthias Gunzer, Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, & Leibniz-Institut für Analytische Wissenschaften - ISAS; Dr Bert Klebl, Khanu GmbH on behalf of KHAN-I GmbH & Co. KG (KHAN-I) and Lead Discovery Center GmbH (LDC)
Max Planck Innovation
Challenge
Ischemic stroke remains a leading cause of death and long-term disability worldwide, with limited causal treatment options beyond reperfusion strategies such as thrombolysis or thrombectomy. A major unmet need is the prevention of secondary inflammatory brain damage following ischemia/reperfusion, including thrombo-inflammation and blood–brain barrier (BBB) disruption. Neutrophil extracellular traps (NETs) are recognized as key drivers of stroke pathology, promoting clot stabilization, resistance to tissue plasminogen activator (tPA), vascular injury and neuroinflammation. Current experimental approaches such as DNase treatment target NETs downstream but are associated with increased hemorrhagic risk. Safer upstream interventions that prevent pathological NET formation without compromising vascular integrity are therefore urgently needed.
Technology
Gasdermin D (GSDMD) is a key effector protein in neutrophil extracellular trap (NET) formation and inflammasome-associated signaling. Although GSDMD is involved in both NETosis and pyroptosis, these processes are mechanistically distinct: pyroptosis involves caspase-mediated GSDMD cleavage, whereas NET formation depends on neutrophil elastase–driven activation. In ischemic stroke, excessive NET formation drives thrombo-inflammation, BBB disruption and secondary brain injury. By inhibiting GSDMD-dependent pore formation upstream of NET release, our approach prevents pathological NETosis before extracellular traps are formed, differentiating it from downstream DNase-based strategies.
Commercial Opportunity
Stroke affects millions of patients annually and remains a major driver of mortality, disability and healthcare costs worldwide. Despite advances in reperfusion therapies, many patients experience poor outcomes due to secondary inflammatory damage. There is currently no approved therapy targeting NETosis or inflammasome-driven thrombo-inflammation in stroke. GSDMD inhibition addresses a validated but therapeutically underexploited mechanism and offers clear differentiation from DNase-based approaches. Given the large patient population and lack of disease-modifying anti-inflammatory therapies, GSDMD inhibitors represent an attractive commercial opportunity.
Development Status
A phenotypic HTS in human primary neutrophils identified multiple potent small-molecule inhibitors of NET formation. Proteomics-based target identification confirmed GSDMD as the molecular target. Lead compounds show sub-micromolar cellular activity, favorable ADME properties and acceptable in vivo pharmacokinetics without significant adverse effects. PoC was demonstrated in a rat transient middle cerebral artery occlusion (tMCAO) model, where GSDMD inhibition reduced infarct size and improved neurological outcome, with efficacy comparable to edaravone. Cellular PoP was established in an ANCA-associated vasculitis model. Independent in vivo validation in neuroinflammation was obtained by a third party using a precursor GSDMD inhibitor in a traumatic brain injury (TBI) model. Lead optimisation and pharmacological profiling are ongoing, prioritising acute ischemic stroke while retaining optionality for selected inflammatory and autoimmune indications.
Patent Situation
Composition-of-matter patent application has been filed recently.
Further Reading
Laridan et al. 2017; Ducroux et al. 2018; Kim et al. 2019; Peña-Martínez et al. 2019; Novotny et al. 2020; Kang et al. 2020; Wang et al. 2021; Denorme et al. 2022; Tuz et al 2024, He et al. 2025
