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 of Medicinal Chemistry
Marta SerafiniSilvia Fallarini

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.

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Citations

Oct 27, 2020·Frontiers in Pharmacology·Long-Fei MaoYue-Ming Li
Dec 21, 2020·European Journal of Medicinal Chemistry·Rahul Singh, Deepak B Salunke
Feb 10, 2021·Journal of Medicinal Chemistry·Ute F RöhrigVincent Zoete
Feb 20, 2021·ACS Medicinal Chemistry Letters·Miyuki KumazawaKenji Matsuno
Mar 28, 2021·Bioorganic Chemistry·Shulun ChenAo Zhang
Nov 20, 2020·Pharmacology & Therapeutics·Ana DolšakMatej Sova
Apr 23, 2021·Journal of Hematology & Oncology·Kai TangBin Yu
Dec 2, 2020·Trends in Pharmacological Sciences·Morgane ModouxHarry Sokol
Jul 23, 2021·Journal of Medicinal Chemistry·Matthew M HamiltonRichard T Lewis
Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pankaj SharmaKarl A Werbovetz
Jul 28, 2021·Archiv der Pharmazie·Menna A EwidaHussein I El-Subbagh

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