Drugs targeting the IL-23-Th17 pathway in immune-mediated inflammatory diseases


We are developing a new class of antiinflammatory drugs dedicated to immune-mediated inflammatory diseases (IMID) a heterogeneous group of diseases characterized by acute or chronic inflammation affecting any organ system whose physiopathology includes imbalance of inflammatory cytokines. IMID cause high morbidity and represent a considerable burden on patients in terms of altered quality of life and on society. We discovered 2,4-D a natural anti-inflammatory compound targeting the IL-23/IL-17 axis and identified its cellular targets in vitro and its efficacy in preclinical models of IMID (creation of a startup and patent filed). Our project aims to identify the molecular targets of 2,4-D, to use medicinal chemistry for R&D, and to complete the pre-clinical study in a flagship animal model of IMID, Crohn's disease, and in ALS a model of deadly neurodegenerative disease with a strong inflammatory component The aim is to speed up the timeliness for a phase I study.

We discovered that 2,4-D suppresses at micromolar concentration the lipopolysaccharide (LPS)-induced production of Th17 signature cytokines and chemokines in human immune cells. This compound inhibits the release of the Th17-activating cytokine IL-23 (Figure 1). However, several observations indicate that it likely acts on more than just one molecular pathway (for example on downstream effects of IL-23 enhanced production). 2,4-D was successfully validated as a potent anti-inflammatory drug in 6 different pre-clinical models of IMID (patent pending).

The IMIDRUG project is funded by the ANR and the Pre-maturation program of the Université de Paris. It involves two teams of the Institut Cochin (Stefano Marullo & Bruno Lucas), one team at the Faculté de Pharmacie (Michel Vidal), and one team of the Saints-Pères, Paris Institute for the Neurosciences (SPPIN) Laboratory (Daniel Zytnicki).

The project includes three principal aims:

  • The identification of 2,4-D (and derived compounds) molecular targets that mediates its anti-inflammatory properties
  • The evaluation of 2,4-D as a of motor neuron degeneration inhibitor in a mouse model of Amyotrophic Lateral Sclerosis
  • The evaluation of the 2,4-D anti-inflammatory effect in pre-clinical models of Multiple Sclerosis and Crohn disease

The company associated to this project (ALLSPIM) founded by Jean-Marie Andrieu and Wei Lu in 2017, is currently raising additional funds to cover the industrial expenses of the project, including: pharmaco-kinetics, metabolism, pharmacotoxicity, production of synthetic 2,4-D and derived compounds (GMP) for Phase I studies.

Schéma Projet 1 équipe Marullo pathways modulated by 2,4-D