肿瘤坏死因子超家族蛋白质相互作用：小分子调节的可行性

Title:TNF Superfamily Protein-Protein Interactions: Feasibility of Small- Molecule Modulation

Volume: 16 Issue: 4

Author(s): Yun Song and Peter Buchwald

Affiliation:

关键词: CD40，协同信号，成药性，OX40，肿瘤坏死因子。

摘要: 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.

Cite this article as:

Yun Song and Peter Buchwald , TNF Superfamily Protein-Protein Interactions: Feasibility of Small- Molecule Modulation, Current Drug Targets 2015; 16 (4) . https://dx.doi.org/10.2174/1389450116666150223115628