Drug design and synthesis of new anticancer agents

Development of novel modulators of epigenetic targets Mai A., Fioravanti R., Rotili D., Valente S., Zwergel C. The Mai group has extensive expertise in the development of small molecule epigenetic modulators. Their primary goal is to contribute to the search for new treatments for diseases ranging from cancer to metabolic disorders. The targeted epigenetic proteins include the lysine-specific demethylase 1 (LSD1), against which they developed both tranylcypromine-based covalent inhibitors as well as non-covalent ones (e.g., quinazoline-based ones). Another protein family investigated by the Mai group are histone deacetylases (HDACs) against which they have recently reported pyridine-based inhibitors active in leukaemia. Moreover, they have recently developed activators of sirtuins, specifically targeting SIRT3, SIRT5, or SIRT6. Finally, the Mai group also applies native mass spectrometry to assess the influence of small molecules on both protein activity and interactions. Carbonic Anhydrase (CA) inhibitors as antitumor agents Secci D., Chimenti P., Granese A., Guglielmi P. Human carbonic anhydrase (hCA) isoforms IX and XII are over-expressed in solid hypoxic tumors and they are considered a prognostic tool and a therapeutic target for cancer. New derivates, synthesized by our group, based on the saccharin and pyran-2-one cores showed to be endowed with potent and selective inhibitory activity against the tumor-related human carbonic anhydrase isoforms IX and XII in the low nanomolar range. The saccharin and pyran-2-one derivatives exhibiting the best hCA inhibitory activity were further investigated in a tumoral biological in vitro model represented by MCF7 breast adenocarcinoma cells demonstrating to act as chemosensitizer and coadjuvant in combination with doxorubicin. Ferroptosis and DVL1 are promising strategies for anticancer drug development Silvestri R., Coluccia A., La Regina G., Nalli M. An ARDHEP derivative exhibited the hallmarks of ferroptosis and inhibited the cell viability of human GBM U-87 MG and OC OVCAR-3 cells with nanomolar IC50 values. We hypothesize that the novel tubulin polymerization inhibitor may interact with tubulin-associated-voltage-dependent anion channel (VDAC), thereby interfering with the function of the mitochondrial activity. The interaction between tubulin and VDCA has been reported as novel target for inducing ferroptosis in cancer cells. Compound ARDHEP was metabolically stable when incubated with human liver microsomes and showed a medium intrinsic clearance of 36 µL/min/mg protein. Structure-based virtual screening studies led to the discovery of RS4690 as a selective DVL1 inhibitor. The enantiomer (S) showed greater inhibition of DVL1 than the (R)-enantiomer. Binding competition assays and in cells biological evaluation confirmed the mechanism of action, the block of the WNT pathway and the anticancer activity.