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The [1,2,4]Triazolo[4,3‐ a ]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors
Author(s) -
Fallarini Silvia,
Bhela Irene P.,
Aprile Silvio,
Torre Enza,
Ranza Alice,
Orecchini Elena,
Panfili Eleonora,
Pallotta Maria T.,
Massarotti Alberto,
Serafini Marta,
Pirali Tracey
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100446
Subject(s) - in silico , pyridine , rational design , chemistry , virtual screening , combinatorial chemistry , catalysis , enzyme , stereochemistry , active site , selectivity , heme , drug discovery , computational biology , biochemistry , biology , nanotechnology , medicinal chemistry , materials science , gene
Inhibitors of indoleamine 2,3‐dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure‐based virtual screening made on IDO1 active site. The starting hit compound is a novel chemotype based on a [1,2,4]triazolo[4,3‐ a ]pyridine scaffold, so far underexploited among the heme binding moieties. Thanks to the rational and in silico ‐guided design of analogues, an improvement of the potency to sub‐micromolar levels has been achieved, with excellent in vitro metabolic stability and exquisite selectivity with respect to other heme‐containing enzymes.