jm9b01809_si_001.pdf (2.11 MB)
Discovery of Highly Potent Benzimidazole Derivatives as Indoleamine 2,3-Dioxygenase‑1 (IDO1) Inhibitors: From Structure-Based Virtual Screening to in Vivo Pharmacodynamic Activity
journal contribution
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 FallariniIn
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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compoundMDSC-like cellsCYPpancreatic ductal adenocarcinomaL-Kyn levelsVivo Pharmacodynamic Activitypocket Cnanomolar levelnovel classtumoral settingsPotent Benzimidazole DerivativesIDO 1 inhibitorschemistry campaignbenzimidazole substructureStructure-Based Virtual Screeningbinding interactionTDOIDO 1
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