Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2017

Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization

Abstract

Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL- 15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain and/or the proliferation of IL-15-dependent cells. One of them was selected as a hit, optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.

Domains

Cancer
Embargoed file
Embargoed file
Visibility date is undetermined
Loading...

Dates and versions

inserm-01550121 , version 1 (29-06-2017)

Identifiers

Cite

Agnès Quéméner, Mike Maillasson, Laurence Arzel, Benoit Sicard, Romy Vomiandry, et al.. Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization. Journal of Medicinal Chemistry, 2017, 60 (14), pp.6249-6272. ⟨10.1021/acs.jmedchem.7b00485⟩. ⟨inserm-01550121⟩
154 View
4 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More