The [1,2,4]Triazolo[4,3-a]pyridine as a New Player in the Field of IDO1 Catalytic Holo-Inhibitors
| Autor: | Alice Ranza, Enza Torre, Maria Teresa Pallotta, Elena Orecchini, Silvio Aprile, Silvia Fallarini, Tracey Pirali, Marta Serafini, Eleonora Panfili, Alberto Massarotti, Irene Preet Bhela |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Virtual screening
Heme binding Cell Survival medicine.medical_treatment Antineoplastic Agents Biochemistry chemistry.chemical_compound Structure-Activity Relationship 1 2 4-triazole Cancer immunotherapy Indoleamine 2 3-dioxygenase-1 inhibitors Cell Line Tumor Pyridine medicine Humans Indoleamine-Pyrrole 2 3 -Dioxygenase General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Pharmacology chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure Drug discovery Organic Chemistry Active site 1 2 4-Triazole in-silico design Combinatorial chemistry Enzyme chemistry biology.protein Molecular Medicine Drug Screening Assays Antitumor 3-dioxygenase-1 inhibitors 4-triazole Indoleamine 2 |
| Zdroj: | ChemMedChem. 16(22) |
| ISSN: | 1860-7187 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text