Toward the development of small molecules for unconventional targets and diseases

This thesis is focused on the development of small molecules for unconventional targets and diseases: the Store-Operated Calcium Entry (SOCE) machinery, the enzyme indoleamine 2,3 dioxygenase 1 (IDO1) and hereditary multiple exostoses (HME) disease. The SOCE is a specialized form of calcium influx that does not involve voltage, but a close communication between the plasma membrane and the endoplasmic reticulum. Dysfunction in this phenomenon has been associated to a plethora of human disorders. Over the years a growing number of SOCE modulators have been reported; unfortunately, all of them show drawbacks in term of lack of specificity and selectivity. This thesis illustrates the discovery of a novel family of compounds able to fine-tune SOCE. Two promising inhibitors that proved to be effective both ex vivo in biopsies from patients affected by tubular aggregate myopathy (TAM) and in vivo in an animal model of acute pancreatitis, two diseases characterized by a hyperactivation of SOCE, have been reported. Indoleamine 2,3-dioxygenase (IDO1), a key enzyme in tryptophan catabolism, is emerging at the vanguard of druggable targets in cancer immunotherapy. The search for small-molecule inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Nevertheless, to have reached human clinical trial. With the aim to find potent inhibitors developed two classes of compounds bearing an imidazothiazole and a benzimidazole scaffold, respectively. HME is an autosomal dominant disorder characterized by the formation of multiple bony spurs or lumps, known as exostoses, next to long bones and other skeletal elements. A strategy to prevent initiation or retard the growth of exostoses is the development of compounds that enhance HS formation. A class of compounds thật may be considered promising starting points towards the development of probes suitable for in vivo testing will be presented.