The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related
receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors.
Almost all of these cell surface protein-protein interactions (PPIs) represent high-value therapeutic
targets for inflammatory or immune modulation in autoimmune diseases, transplant recipients, or
cancers, and there are several biologics including antibodies and fusion proteins targeting them that are
in various phases of clinical development. Small-molecule inhibitors or activators could represent possible
alternatives if the difficulties related to the targeting of protein-protein interactions by small
molecules can be addressed. Compounds proving the feasibility of such approaches have been identified through different
drug discovery approaches for a number of these TNFSFR-TNFSF type PPIs including CD40-CD40L, BAFFR-BAFF,
TRAIL-DR5, and OX40-OX40L. Corresponding structural, signaling, and medicinal chemistry aspects are briefly reviewed
here. While none of these small-molecule modulators identified so far seems promising enough to be pursued for
clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule
modulation and can serve as starting points toward the identification of more potent and selective candidates.
Keywords: CD40, costimulation, druggability, OX40, tumor necrosis factor.
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