Discovery and development of small molecules targeting IDO1 and SOCE

My PhD thesis is focused on two main projects: the discovery of Store-Operated Calcium Entry (SOCE) modulators and the development of indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. SOCE is a specialized form of calcium influx across the plasma membrane that is induced by the depletion of this ion in the endoplasmic reticulum. Calcium homeostasis is fundamental for cells and alterations of SOCE are linked to pathological conditions, namely acute pancreatitis and a rare disease named tubular aggregate myopathy (TAM). Starting from a class of pyrtriazoles that we published in 2018, with the aim of developing drug-like compounds compatible with the chronic treatment of TAM, we developed two classes of modulators, the 1,2,4-oxadiazole-bearing pyrazoles and the biphenyl triazoles. Our efforts resulted in the identification of a promising lead compound with improved PK profile, in vivo efficacy in a model of acute pancreatitis and ex vivo efficacy in muscles biopsies from a TAM mouse model. IDO1 is a crucial enzyme in tryptophan metabolism and has emerged as a druggable target in cancer immunotherapy due to its role in immune escape. By exploiting multicomponent reactions, our research group has previously reported a class of imidazothiazole-bearing IDO1 inhibitors with a peculiar binding mode in the active site, protruding in a region of the enzyme that we named pocket C. Relying on this peculiar interaction, a second class of imidazothiazoles was synthesised by the click chemistry approach. Moreover, the acquired structural information on pocket C was integrated in a virtual screening that led to the discovery of two hits, VS-13 and VS-15. These compounds have been the starting point of two medicinal chemistry campaigns that resulted in the discovery of a VS-13 analogue able to inhibit IDO1 at the low nanomolar level and to provide a significant reduction of L-Kyn plasma levels in mice, confirming the molecule as a potent IDO1 inhibitor also under in vivo settings.