Natural Fragments in the Design of Modulators of Multiple Targets

A multitude of Natural Products that display diverse biological activities are based on a benzoquinone core.1 Aiming at identifying potential mimetics of the dihydroxymethyl derivative DHMBQ (Figure 1A), we have applied physicochemical descriptors and Principal Component Analysis (PCA) to a database containing nearly 14000 fragments. Upon selection, DHMBQ-like fragments were evaluated for binding to two different targets, namely the BIR3 domain of X-chromosome linked Inhibitor of Apoptosis Protein (XIAP) and the kinase domain of Insulin-like Growth Factor Receptor 1 (IGF-1R). IAPs and IGF-1R are known proteins involved in cell signaling pathways which regulate vital functions in cells, and benzoquinone-containing compounds have been reported as inhibitors of either XIAP or IGF-1R (e.g. 1 and 2, Figure 1A).2,3 A Surface Plasmon Resonance protocol has been used, from which binders of XIAP and IGF-1R were identified (Figure 1B). Guided by a ligand-based rationale, simplified mimetics of 1 and 2 were prepared (Figure 1C), which will be discussed in this communication. Figure 1. A: Embelin (1) and a nakijiquinone-analogue (2), known inhibitors of XIAP and IGF-1R, respectively. B: Examples of potential DHMBQ mimetics identified by PCA. C: Examples of simplified mimetics of 1 and 2. References [1] Drugs of Natural Origin - A Treatise of Pharmacognosy, 6th ed., Samuelsson G., Bohlin, L., Apotekarsocieteten-Swedish Pharmaceutical Society, Swedish Pharmaceutical Press, 2009, Stockholm, Sweden; Owton, W. M., J. Chem. Soc., Perkin Trans. 1, 1999, 17, 2409-2420. [2] Mace, P. D. et al., Cell Death Differ., 2010, 17, 46-53; Wu, J. et al., EMBO J., 2008, 27, 1985-1994. [3] Nikolovska-Coleska, Z. et al., J. Med. Chem., 2004, 47, 2430-2440; Stahl, P. et al., Angew. Chem. Int. Ed., 2002, 41, 1174-1178.