Small Molecules as Anti-TNF Drugs

Abstract

Tumor necrosis factor (TNF, TNF-α, cachectin) is a pleiotropic, proinflammatory cytokine with multiple biological effects, many of which are not yet fully understood. Although TNF was initially described as an anti-tumor agent more than three decades ago, current knowledge places it central to immune system homeostasis. TNF plays a critical role in host defense against infection, as well as an inhibitory role in autoimmune disease. However, TNF overproduction generates deleterious effects by inducing the transcription of genes involved in acute and chronic inflammatory responses including asthma, rheumatoid arthritis, Crohn's disease, and psoriasis. Direct inhibition of TNF by biologics, such as monoclonal antibodies and circulating TNF receptor constructs, has produced effective treatments for these disorders and validated the inhibition of this proinflammatory cytokine as an effective therapy. Unfortunately, these biological therapies suffer from several drawbacks, including high cost and the induction of autoantibody production. Thus, the development of small molecules able to modulate TNF production or signaling pathways remains a central challenge in Medicinal Chemistry. Considerable efforts have been made over the past two decades to develop such inhibitors, which could potentially be administered orally and would presumably be cheaper. This review is focused on the recent development of compounds that modulate the activity of this cytokine by acting at different levels, such as TNF expression, processing, binding to its receptors and direct inhibition. These approaches will be compared and discussed.

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

“…Although the first of the TNFR2 inhibitors identified was thalidomide ( 62 ), recent research actually focused on the development of TNFR2-targeting biological agents. This may be because the difficulty to block TNF–TNFR interaction with a small molecule, due to the large contact surface area ( 90 ), and due to the apparent advantage of biological therapeutics, such as high target specificity, well-understood mechanism and minimal toxicity ( 91 , 92 ). Nevertheless, cell-permeable small molecules may also effectively block TNFR2 signaling pathways, and consequently inhibit Treg activity induced by TNF–TNFR2 interaction.…”

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

“…Approaches have also been described using natural products such as Japonicone A 10 , and others have targeted the receptor rather than the TNF ligand 11,12 . The status of small molecule inhibitors of TNF has been reviewed in a number of articles 13,14 .…”

In Silico Identification and Evaluation of Natural Products as Potential Tumor Necrosis Factor Function Inhibitors Using Advanced Enalos Asclepios KNIME Nodes

“…TNF has been broadly studied and reviewed in the literature [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ], underlining the importance and the relevance of this growth factor as a valuable drug target.…”

“…However, these antagonists are mainly biologics, i.e., monoclonal antibodies (infliximab, adalimumab, certolizumab pegol, golimumab) [ 7 , 14 , 15 ] and fusion proteins (etanercept) [ 16 ], which bear certain drawbacks. Such disadvantages include causing hypersensitivity, increased risk of patients to develop serious infections, such as tuberculosis and hepatitis B because of the caused immune system suppression, loss of patients’ response during therapy due to arisen immunogenicity, and intravenous/subcutaneous administration as well as high cost of production and supply [ 8 , 10 , 11 , 17 , 18 , 19 , 20 , 21 , 22 ]. Thus, there is a great need for the development of potent small molecules that will efficiently inhibit TNF activity, as they can be inexpensively produced and distributed; they can be formulated to accommodate a plethora of administration routes (e.g., per os) while they can also present lower immunosuppressive side effects than biologics [ 8 , 10 , 11 , 21 ].…”