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

Enza Torre, M Serafini, S Aprile, ED Grosso, A Gesù, A Griglio, G Colombo, C Travelli, S Paiella, A Adamo, E Orecchini, A Coletti, MT Pallotta, S Ugel, A Massarotti, T Pirali, S. Fallarini

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

Abstract

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.
Lingua originaleEnglish
pagine (da-a)3047-3065
Numero di pagine19
RivistaJournal of Medicinal Chemistry
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • Cancer immunotherapy
  • indoleamine 2,3-dioxygenase 1

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