期刊
CHEMMEDCHEM
卷 16, 期 22, 页码 3439-3450出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100446
关键词
Drug discovery; Indoleamine 2; 3-dioxygenase-1 inhibitors; 1; 2; 4-triazole; Virtual screening; in-silico design
资金
- Fondazione AIRC (Associazione Italiana per la Ricerca sul Cancro) fellowship for Abroad [25278]
- Ministero dellIstruzione, dellUniversita e della Ricerca (MIUR) [2017WJZ9W9]
- Politecnico di Milano within the CRUI-CARE Agreement
Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy, and recent studies have revealed additional roles of IDO1 beyond its catalytic activity. A novel class of compounds, originated from a structure-based virtual screening on IDO1 active site, has shown improved potency, metabolic stability, and selectivity after rational and in silico-guided design of analogues.
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.
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