The [1, 2, 4]Triazolo[4, 3‐a]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors. (27th August 2021)

• Record Type: Journal Article
• Authors: Fallarini, Silvia; Bhela, Irene P.; Aprile, Silvio; Torre, Enza; Ranza, Alice; Orecchini, Elena; Panfili, Eleonora; Pallotta, Maria T.; Massarotti, Alberto; Serafini, Marta; Pirali, Tracey
• Is Part Of: ChemMedChem. Volume 16:Number 22(2021)
• Page Start: 3439
• Page End: 3450
• Publication Date: 2021-08-27
• Subjects: Drug discovery -- Indoleamine 2, 3-dioxygenase-1 inhibitors -- 1, 2, 4-triazole -- Virtual screening -- in-silico design; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100446
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : A new player has joined the field of IDO1 catalytic holo‐inhibitors: From a structure‐based virtual screen, a hit compound displaying an atypical [1, 2, 4]triazolo[4, 3‐ a ]pyridine ring as the heme‐binding scaffold was identified. The in silico ‐guided design of analogues led to the identification of an IDO1 inhibitor with sub‐micromolar potency, high metabolic stability and selectivity over TDO and CYP enzymes.