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Discovery of Highly Potent Benzimidazole Derivatives as Indoleamine 2,3-Dioxygenase‑1 (IDO1) Inhibitors: From Structure-Based Virtual Screening to in Vivo Pharmacodynamic Activity

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posted on 2020-03-17, 10:13 authored by Marta Serafini, Enza Torre, Silvio Aprile, Erika Del Grosso, Alessandro Gesù, Alessia Griglio, Giorgia Colombo, Cristina Travelli, Salvatore Paiella, Annalisa Adamo, Elena Orecchini, Alice Coletti, Maria Teresa Pallotta, Stefano Ugel, Alberto Massarotti, Tracey Pirali, Silvia Fallarini
In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.

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