Isolated from the marine sponge Spongionella gracilis and a member of the diterpene family, Gracilin A possesses a bisacetoxy tricyclic structure.¹ Gracilin A is an inhibitor of cyclophilins A (CypA) and D (CypD) with IC₅₀ values of 0.26 μM for CypD and 0.27 μM CypA, respectively. Inhibition of CypA has been shown to yield immunosuppression and inhibitors of CypD have been shown to provide neuroprotective effects.^2,3  Gracilin’s novel structure and potent biological activity have prompted considerable synthetic and biological interest.

Prototypical chemotherapeutic agents for cancer treatment are based on the concept of “one-drug, one-target, one-disease”, but most forms of cancer have the ability to develop resistance mutations or are able to up-regulate targeted proteins to elude treatment with a single therapeutic agent. Polypharmacology, previously considered undesirable for a drug, has re-emerged as an approach to cancer therapy by acting on multiple targets or cellular pathways.¹ Anticancer drugs displaying polypharmacology are thought to evade drug resistance due to the need for cells to become resistant across multiple pathways through simultaneous protein/enzyme mutations.