Abstract
Tumor necrosis factor (TNF) –related apoptosis-inducing ligand (TRAIL) is an immuno-surveillance cytokine that is expressed in various tissues and cells [1, 2]. The expression of TRAIL on immune cells plays a role in immune surveillance in the prevention of tumors and metastasis [3]. TRAIL is attractive as an anti-tumor agent because of its capability to induce apoptosis in cancer cells by activating death receptors 4 and 5 (DR4 and DR5) with little toxicity against normal cells [2]. Despite its robust cell killing of tumor cells in vitro, efficacy of TRAIL receptor agonists has been limited in clinical trials, and this limited activity is thought to be due to lack of reliable predictive biomarkers of sensitivity and drug properties that limit efficacy such as short serum half-life, stability, and bio-distribution [3, 4].
Highlights
Tumor necrosis factor (TNF) –related apoptosisinducing ligand (TRAIL) is an immuno-surveillance cytokine that is expressed in various tissues and cells [1, 2]
This has led to planned clinical development of TRAIL-inducing compound 10 (TIC10)/ONC201 by Oncoceutics
Subsequent NMR and X-ray crystallographic analyses of the original TIC10/ONC201 compound from the National Cancer Institute (NCI) library determined the active agent to be an isomer with an angular tricyclic core (Figure 1, active compound, tricyclic core highlighted in bold) [6]
Summary
Tumor necrosis factor (TNF) –related apoptosisinducing ligand (TRAIL) is an immuno-surveillance cytokine that is expressed in various tissues and cells [1, 2]. To overcome the lack of activity of exogenous TRAIL ligands, Allen et al conducted a screen using a colon cancer cell line to identify small molecules in a National Cancer Institute (NCI) chemical library that could induce TRAIL on tumor cells and thereby activate TRAIL receptors via an autocrine or paracrine mechanism [5]. This screen identified TRAIL-inducing compound 10 (TIC10; known as ONC201 and NSC350625).
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