Periodic Reporting for period 1 - IMMUNOSTIM (Novel small molecule activators of the NLRP3 inflammasome as immunostimulants)
Periodo di rendicontazione: 2021-09-01 al 2023-02-28
Propper immune function protects us from invading pathogens and eliminates cancer cells, while aberrant immune responses can damage our body’s tissues. Diseases connected to too much or too little immunity are an increasing societal challenge. Novel drugs to precisely control immunity and optimize the intensity of responses are being developed. The already available suppressive and stimulatory drugs have demonstrated their clinical potential in rheumatologic diseases or cancer therapy, respectively, but are often not very specific and have side effects. In addition, the available drugs are directed against a limited number of targets. To fully tab into the potential of controlling immunity and to minimize side effects of immune suppression or autoimmunity, drugs regulating additional targets are required. The NLRP3 inflammasome is a highly promising target for modulation in either direction. We screened for and identified novel substances triggering NLRP3 with the dual goal to identify new immunostimulatory drug candidates, and to gain new insights into the elusive activation mechanism of NLRP3 as a basis for a rational development of activators or inhibitors. Within this project, we pursued their development as immunostimulatory drugs to break cancer immune evasion. To understand the precise mode-of-action of our drugs, we elucidated direct interaction partners and proteins whose presence is required for activity. In an approach known as establishing structure-activity-relationship, we identified the specific chemical features required for on-target activity by testing a large number of similar compounds. After optimizing drug formulation, lead compounds were tested in preclinic models to establish toxicity, and immunostimulatory and anti-tumour activity. The results we obtained are encouraging, and we pursue further development towards the market.