Small-molecule modulators of tumor necrosis factor signaling

Henri Chédotal; Dilip Narayanan; Katrine Povlsen; Charlotte H Gotfredsen; Roberta Brambilla; Michael Gajhede; Anders Bach; Mads H Clausen

doi:10.1016/j.drudis.2023.103575

Small-molecule modulators of tumor necrosis factor signaling

Drug Discov Today. 2023 Jun;28(6):103575. doi: 10.1016/j.drudis.2023.103575. Epub 2023 Mar 30.

Authors

Henri Chédotal¹, Dilip Narayanan², Katrine Povlsen², Charlotte H Gotfredsen³, Roberta Brambilla⁴, Michael Gajhede², Anders Bach⁵, Mads H Clausen⁶

Affiliations

¹ Technical University of Denmark, Center for Nanomedicine and Theranostics, Department of Chemistry, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark.
² Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
³ Technical University of Denmark, Department of Chemistry, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark.
⁴ The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurobiology Research, Institute of Molecular Medicine, and BRIDGE - Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense 5230, Denmark.
⁵ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: anders.bach@sund.ku.dk.
⁶ Technical University of Denmark, Center for Nanomedicine and Theranostics, Department of Chemistry, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark. Electronic address: mhc@kemi.dtu.dk.

PMID: 37003513
DOI: 10.1016/j.drudis.2023.103575

Abstract

Tumor necrosis factor (TNF) is a pleiotropic cytokine with a major role in immune system homeostasis and is involved in many inflammatory and autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis, Alzheimer's disease (AD), and multiple sclerosis (MS). Thus, TNF and its receptors, TNFR1 and TNFR2, are relevant pharmacological targets. Biologics have been developed to block TNF-dependent signaling cascades, but they display serious side effects, and their pharmacological effectiveness decreases over time because of their immunogenicity. In this review, we present recent discoveries in small molecules targeting TNF and its receptors and discuss alternative strategies for modulating TNF signaling.

Keywords: inflammatory diseases; small molecules; tumor necrosis factor; tumor necrosis factor receptors.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid*
Autoimmune Diseases* / drug therapy
Cytokines
Humans
Multiple Sclerosis*
Receptors, Tumor Necrosis Factor, Type I / therapeutic use
Tumor Necrosis Factor-alpha

Substances

Receptors, Tumor Necrosis Factor, Type I
Cytokines
Tumor Necrosis Factor-alpha