Identification of small-molecule protein-protein interaction inhibitors for NKG2D.

Autor:	Thompson AA; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Harbut MB; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Kung PP; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Karpowich NK; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Branson JD; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Grant JC; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Hagan D; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Pascual HA; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Bai G; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Zavareh RB; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Coate HR; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Collins BC; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Côte M; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Gelin CF; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Damm-Ganamet KL; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Gholami H; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Huff AR; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Limon L; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Lumb KJ; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Mak PA; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Nakafuku KM; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Price EV; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Shih AY; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Tootoonchi M; Discovery Immunology, Janssen Research & Development, San Diego, CA 92121., Vellore NA; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Wang J; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Wei N; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Ziff J; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Berger SB; Discovery Immunology, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Edwards JP; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Gardet A; Discovery Immunology, Janssen Research & Development, San Diego, CA 92121., Sun S; Discovery Immunology, Janssen Research & Development, San Diego, CA 92121., Towne JE; Discovery Immunology, Janssen Research & Development, San Diego, CA 92121., Venable JD; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Shi Z; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Venkatesan H; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Rives ML; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Sharma S; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002., Shireman BT; Therapeutics Discovery, Janssen Research & Development, San Diego, CA 92121., Allen SJ; Therapeutics Discovery, Janssen Research & Development, Lower Gwynedd Township, PA 19002.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 May 02; Vol. 120 (18), pp. e2216342120. Date of Electronic Publication: 2023 Apr 25.
DOI:	10.1073/pnas.2216342120
Abstrakt:	NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ + , and CD8 + T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.
Databáze:	MEDLINE
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