Angel Rodriguez Nebreda & María Macías

Institut de Recerca Biomèdica

p38 is a protein kinase that regulates many cellular functions and has been implicated in diseases such as chronic inflammation, immunological disorders, or cancer. To date, it has been difficult to find p38 inhibitors for use in clinical practice because the candidates produce toxic effects that preclude their administration at adequate therapeutic doses.

We have generated a new type of p38 inhibitor, which preferentially impairs one of the activation pathways of this protein. In particular, these inhibitors block the self-activation (or autophosphorylation) of p38 but allow it to be activated by other mechanisms.

The project was developed by a multidisciplinary team at IRB Barcelona. Computational techniques were used by Orozco’s group and the IRB Barcelona spin-off Nostrum Biodiscovery to perform virtual screenings and in silico hit optimization studies that allowed the identification of potential inhibitors of p38. About 100 of these compounds were characterized by Nebreda’s group using a range of biochemical assays to identify p38 autophosphorylation inhibitors. Crystallography techniques performed by Macías’ group revealed how the inhibitors bind to the p38 protein shedding light on their mechanism of action.

The new inhibitors compete with the ATP molecule to bind to the active centre of p38, but do not have very high affinity. So as soon as the protein is activated by an external factor, ATP displaces the inhibitor and p38 can exert its normal functions. The identification of compounds that selectively inhibit some p38 functions can potentially reduce the side effects associated with its total inhibition, providing an opportunity to develop new therapeutic strategies.

The pathway blocked by the new inhibitors is thought to be involved in cardiac cell death caused by the lack of blood supply and subsequent restoration that occur after myocardial infarction, as well as in the heart damage caused by treatment with some anti-tumor chemotherapeutics