The aim of the project is the development of compounds with selective inhibition against the heparanase enzyme and their evaluation as modulators in autophagy. This group has already identified: i) a class of benzoimidazoles that inhibit heparanase. This is a strong basis for rational drug design of specific Heparanase inhibitors.
Heparanase (Hpse) is the only known mammalian endo-ß-D-glucuronidase capable of cleaving heparan sulphate residues of proteoglycans, an activity highly implicated in a wide variety of biological processes . More recently, the role of Hpse in modulating autophagy in normal and malignant cells has been established thereby conferring growth advantages as well as resistance to chemotherapy.. Autophagy may represent a functional processing event creating a substrate for autoreactivity. It follow that the research in this field may contribute to clarify whether endogenous or pharmacological regulation of autophagy might aid in the development of new treatments for human diseases in which autophagy is not functioning properly.
The strategy of this proposal, starting from the molecular mechanisms involved in the early steps of autophagy, will allow to enlighten the role of the autophagic process in the pathogenesis of human diseases, implementing a rational drug design approach to discover and develop new drug compounds. In this context, a central role is played by Hpse enzyme, responsible of modulating autophagy in normal and malignant cells. Hpse functions to promote autophagy and tumor growth and to provide cancer cells with stress resistance, and chemoresistance that is mediated by increased autophagy. Moreover, Hpse expression is induced in many types of cancer and increased Hpse levels are often associated with enhanced tumor growth and metastasis. Inhibiting Hpse, therefore, can reduce both its protumorigenic functions and its induction of resistance to chemotherapy. Despite being an attractive drug target, no drug able to inhibit or modulate Hpse functions has been registered so far and only four polysaccharide derivatives have reached the clinical trial phase. These compounds are characterized by various limitations, underlying the need for effective small molecule Hpse inhibitors.
The combined data from the multidisciplinary approaches described above will enlighten the molecular mechanisms controlling the upstream subtle regulation of autophagy, key process in cell metabolism and stress response and their involvement in several human diseases. The targets and compounds identified will create the basis for the development of novel types of drugs targeting cellular catabolism. Moreover, we expect to identify novel interactors of the given molecules and their targets turning out to be required in the ontogenesis or progression of neurodegeneration or cancer diseases.
The overall methodology and associated work plan of the project proposal starts from a methodological approach aimed to develop new drug leads through successive rounds of Cyclic Process for Drug Development (CPDD) (i.e. consecutive rounds of compound docking, design, synthesis, biochemical and cellular assays and SAR studies). The drug discovery process starts from the identification of hits and their biological properties definition, then a hit-to-lead optimization process to achieve optimized lead compounds. The lead identification will be achieved through phenotypic screening, drug repurposing and target-based screening. The hit optimization process will rely on a multidisciplinary approach involving design and synthesis, enzymatic assays, and in vitro evaluation.
In the view of above, this proposal will largely contribute to the advancement of knowledge with respect to the state of the art. In particular, this project will lead to the discovery of novel lead compounds as Hpse inhibitors with implemented efficacy and safety profile. New chemical entities will be patented and new publications will be submitted depending on the results Moreover, our multidisciplinary strategy will contribute to elucidate the molecular mechanisms controlling the upstream subtle regulation of autophagy.