Chemical Biology and Therapeutics Discovery
Research information
Background
Cells change their identity and behaviour in response to developmental signals, injury and disease. These transitions allow tissues to regenerate and immune cells to respond to threats, but they can also enable cancer cells to adapt and resist treatment. Understanding how these processes are controlled can reveal opportunities for therapeutic intervention.
Our laboratory uses small molecules to investigate the mechanisms governing these cellular transitions and explore new therapeutic strategies. We begin with phenotypic screening, testing compounds for their ability to produce a desired cellular response. We then combine chemical proteomics with molecular, cellular and structural studies to identify their targets and understand how they work.
These molecules serve both as tools to uncover biological mechanisms and as starting points for therapeutic discovery. Through medicinal chemistry and evaluation in relevant experimental models, we assess their potential to modulate immunity, promote myelin repair and selectively target cancer cells.
Research lines
1. Chemical control of immunity and inflammation
We investigate the molecular mechanisms regulating innate and adaptive immunity and develop small-molecule approaches to modulate immune responses in cancer and inflammatory diseases. A major focus is the cGAS–STING pathway, a central component of cytosolic DNA sensing that links genomic instability and cellular stress to type I interferon production and inflammatory signalling.
Our research explores the pharmacological activation and inhibition of this pathway, including the development of non-nucleotide STING agonists and the identification of previously unrecognised regulatory mechanisms controlling cGAS–STING signalling. We combine unbiased phenotypic screening, chemical genetics, medicinal chemistry, structural biology and chemoproteomics to characterise molecular targets and define mechanisms of action.
In parallel, we investigate the chemical modulation of adaptive immune cell function, including the enhancement of gamma delta T-cell antitumour activity and the regulation of regulatory T-cell differentiation. We also study mechanisms controlling immune checkpoint protein expression in the tumour microenvironment. These approaches aim to identify new therapeutic opportunities for cancer immunotherapy and the treatment of immune-mediated inflammatory diseases.
2. Remyelination and multiple sclerosis
We investigate the molecular and metabolic mechanisms governing oligodendrocyte differentiation and myelin regeneration, with the aim of developing regenerative therapies for multiple sclerosis and other demyelinating disorders. Impaired differentiation of oligodendrocyte precursor cells (OPCs) limits endogenous remyelination, particularly during progressive stages of multiple sclerosis.
Our research uses high-content phenotypic screening of primary OPCs to identify small molecules that promote their differentiation into mature, myelin-producing oligodendrocytes. We combine chemical genetics, metabolomics and mechanistic studies to characterise the signalling pathways and metabolic processes controlling oligodendrocyte maturation. Previous work has identified muscarinic receptor signalling and the regulation of serine availability for myelin glycosphingolipid biosynthesis as mechanisms influencing this process.
We also investigate the combined activity of small molecules targeting complementary differentiation mechanisms and evaluate their capacity to promote remyelination in experimental models of demyelinating disease. Our objective is to identify pharmacological strategies that restore endogenous myelin regeneration and complement existing immunomodulatory therapies.
3. Chemical targeting of cancer cell states
We investigate the molecular vulnerabilities associated with distinct cancer cell states, particularly those linked to cellular plasticity, metastatic potential and therapeutic resistance. Our research focuses on mesenchymal and drug resistant cell states, which can exhibit reduced sensitivity to conventional anticancer treatments.
We employ cell-state-selective phenotypic screening, medicinal chemistry, chemical proteomics and genetic approaches to identify compounds that preferentially eliminate aggressive cancer cell populations and elucidate their molecular mechanisms of action. Previous studies have identified small molecules that selectively induce cell death in patient-derived glioblastoma cell through mechanisms involving receptor-interacting protein kinase 2 (RIPK2), as well as compounds targeting the intermediate filament protein vimentin, leading to mitotic disruption in mesenchymal cancer cells.
By integrating target identification, structure–activity relationship studies and functional validation in relevant cancer models, we aim to identify previously unrecognised therapeutic vulnerabilities and develop chemical probes and pharmacological strategies against aggressive and treatment-resistant tumours.