Identification of inhibitors of sterol transport proteins through the synthesis of a cholic acid-inspired compound collection Frederik Simonsen Bro, Laura Depta, Luca Laraia Technical University of Denmark, Denmark Sterol transport proteins (STPs) all bind and transport sterols, and have high structural similarities, particularly in their sterol-binding domain (SBD). 1 Despite these similarities, STPs possess distinct tissue distributions as well as intracellular localisation and functions. Furthermore, STPs not only mediate intracellular sterol transport but also organelle contacts and lipid metabolism more generally. Their misregulation has been associated with lipid storage disorders, atherosclerosis, and a wide range of cancers. 2 Therefore, the development of selective small molecule STP inhibitors is of great significance for both basic and translational lipid biology. Crucially, very few STP inhibitors have been reported, often with little or no selectivity annotations, and the majority of these target a small fraction of STPs, highlighting a significant gap in the field. The pseudo-natural product (PNP) strategy has proven efficient in the identification of active molecules including inhibitors of STPs. 3,4 Thus, this strategy was applied to design and synthesise a compound collection of small molecules inspired by cholic acid in order to identify new STP inhibitors. The cis decalin scaffold as found in cholic acid was used as the primary sterol scaffold to act as a "bait" for STPs. The primary scaffold was fused with natural product fragments (the secondary scaffolds) resulting in heterocyclic edge- and spiro-fused and ring- distorted analogues. The analogues have been thoroughly characterised including several crystal structures. The biological activity of the analogues has been tested against a panel of different STPs by fluorescence polarisation (FP) and differential scanning fluorimetry (DSF). An interesting scaffold obtained by an oxidative ring contraction followed by a spontaneous intramolecular condensation was identified as a selective and potent new chemotype Aster-A inhibitor.
Figure 1 :The identification of Aster-A inhibitors through the synthesis of a cholic acid-inspired compound collection. References 1. J. Luo, L. Y. Jiang, H. Yang and B. L. Song, Trends Biochem. Sci. , 2019, 44 , 273–292. 2. U. Soffientini and A. Graham, Clin. Sci. , 2016, 130 , 1843–1859. 3. T. Whitmarsh-Everiss, A. H. Olsen and L. Laraia, Angew. Chem. Int. Ed. , 2021, 60 , 26755–26761. 4. T. Whitmarsh-Everiss, Z. Wang, C. H. Hansen, L. Depta, E. Sassetti, O. R. Dan, A. Pahl, S. Sievers and L. Laraia, ChemBioChem , 2023, 24 , e202200555.
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