Modern drugs are molecules that interfere with the activity of a specific protein related to a target disease. Within this realm, new molecules capable of interfering with protein-protein interactions (PPIs) are in the heart of modern drug discovery. However, the discovery or de-novo design of new molecules is often hampered by the lack of structural information of the PPI interfaces and suitable experimental binding techniques. This often prompted the conclusion that PPIs are “undruggable” targets. By fostering a multidisciplinary collaboration, we are able to identify new small molecules capable of interfering with PPIs.
This invention relates to immune signaling and specifically, the inhibition of calcineurin-NFAT interaction. Calcineurin is a protein phosphatase that regulates the initiation of the immune response. As such, calcineurin is an important target for immunosuppressive therapy. Although clinically approved drugs of calcineurin exist (Cyclosporine A and Tacrolimus), they have undesirable side effects such as nephrotoxicity and hepatotoxicity. Thus, the ongoing search for drugs that inhibit calcineurin with higher specificity and reduced toxicity is desired. However, the interaction of calcineurin with its substrates is structurally challenging, preventing the application of classical drug-discovery approaches.

Herein, we identified new small molecules capable of interfering with calcineurin-NFAT interaction. These molecules pave the way for the development of new therapeutics such as immunosuppressants (transplantations, psoriasis, and more).
UNMET NEED
The development of safe orally available immune suppression drugs

OUR SOLUTION
Small molecules interfering with calcineurin protein-protein interactions

APPLICATIONS
Immunosuppressant agent for organ transplants.
Autoimmune disorders (e.g., Rheumatoid arthritis, Psoriasis, Lupus and Type 1 diabetes)
Anti-fungal agent.

STATUS
In-vitro validated NCEs have been identified and are under further investigation.

INTELLECTUAL PROPERTY
The structural features of the molecules are confidential
Provisional patent is in preparation for selected chemical scaffolds

REFERENCES
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010874