Identification of Inhibitors of Cholesterol Transport Proteins Through the Synthesis of a Diverse, Sterol‐Inspired Compound Collection

Abstract

Cholesterol transport proteins regulate av ast array of cellular processes including lipid metabolism, vesicular and non-vesicular trafficking,o rganelle contact sites,a nd autophagy.D espite their undoubted importance,t he identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site.H erein we report ag eneral strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of adiverse sterol-inspired compound collection. Fusion of ap rimary sterol fragment to an arrayo f secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C,w hich displayed as urprising preference for the unnatural-sterol AB-ring stereochemistry and new inhibitors of Aster-A. We propose that this strategy can and should be applied to any therapeutically relevant sterol-binding protein.

Identification of Biologically Diverse Tetrahydronaphthalen‐2‐ols through the Synthesis and Phenotypic Profiling of Chemically Diverse, Estradiol‐Inspired Compounds

“…However, we could show that varying the secondary fragment drastically changes the biological activity, thus suggesting that selectivity for a given biological process can be obtained even when starting from a relatively promiscuous primary fragment. This is in line with our own work on sterol transport proteins, where the fusion of a primary steroidal fragment to diverse secondary fragments provided selective modulators of individual sterol transport proteins [3] . This new work reinforces this concept and shows that the same selectivity can be identified even when screening phenotypically, rather than in a target‐based approach.…”

“…Therefore, to unlock the full potential of the pseudo‐NP concept while maintaining synthetic accessibility within a given library synthesis, a careful balance between the number of fragments combined, as well as the number of analogues for each combination, is required. In this context, we have recently proposed the use of natural product inspired primary fragments, which are suitably functionalized to enable the rapid fusion with up to 15 secondary fragments [3] . Employing this strategy to synthesize three to five analogues per fragment fusion enabled the identification of potent and selective inhibitors of different members of the Aster family of cholesterol transport proteins, where the specific secondary fragment fusion dictated the selectivity for a given sterol transport protein.…”

Complexity‐to‐Diversity and Pseudo‐Natural Product Strategies as Powerful Platforms for Deciphering Next‐Generation Therapeutics

“…[104] These findings demonstrate the power of utilizing nature-inspired architectures in a CtD strategy to generate a skeletally and stereochemically diverse compound collections leading to novel chemotypes. [70,101,[105][106][107]…”