The Pseudo‐Natural Product Rhonin Targets RHOGDI

Abstract

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment‐based design. We describe the de novo combination of different 5‐membered NP‐derived N‐heteroatom fragments to structurally unprecedented “pseudo‐natural products” in an efficient complexity‐generating and enantioselective one‐pot synthesis sequence. The pseudo‐NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP‐derived chemotypes, and may have novel biological targets. Investigation of the pseudo‐NPs in unbiased phenotypic assays and target identification led to the discovery of the first small‐molecule ligand of the RHO GDP‐dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP‐bound RHO GTPases and alters the subcellular localization of RHO GTPases.

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

“…[48][49][63][64]108,[110][111] This innovative strategy allows for the access of underdeveloped chemical space that targets biomacromolecules which are not usually targeted by the parent NPs leading to the discovery of chemical probes against unmet needs. [48][49]63,108,[112][113] Biological activities of pseudo-NPs are usually assessed using "unbiased assays", that involve screening against biological systems instead of monitoring a single target in a phenotypic screen. [49,64,108,110,114] For example, phenotypic screening of pseudo-NP identified first-in-class chemical probes such as the chromopyrones 105 that possesses a dual inhibition of glucose transporters GLUT-1/3 as well as exhibiting anticancer activity by inhibiting cancer cells growth.…”

“…Usually, pseudo‐NPs possess bioactivities independent from their parent NPs [48–49,63–64,108,110–111] . This innovative strategy allows for the access of underdeveloped chemical space that targets biomacromolecules which are not usually targeted by the parent NPs leading to the discovery of chemical probes against unmet needs [48–49,63,108,112–113] …”

“…Rhonin 121 a was found to possess an IC 50 value of 1.5 μM as an inhibitor of RHOGDI1, (Scheme 9). [113] …”

Identification of Readily Available Pseudo-Natural Products

“…For instance, we identified novel pseudo-NP inhibitors of glucose transporters 10 , kinases 11,12 , and the first inhibitors of the cholesterolshuttling protein GRAMD1A 13 and the Rho-protein chaperone Rho-GDI. 14 In order to unravel whether the synthesis and biological evaluation of PNPs might have been explored in a wider sense before, for instance driven by intuitive inclusion of NP structures in compound library design, we recently developed the natural product fragment combination (NPFC) tool. This tool allows the identification and classification of PNPs in large compound collections by identifying NP fragments and their combination types in chemical structures.…”

Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone

“…Accordingly, pseudo‐NP collections may explore new regions of biologically relevant chemical space and be enriched with unexpected and/or novel bioactivities. [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ] This concept may be considered the synthetic analogue of recombination of existing biosynthetic pathways to access novel NP‐like scaffolds, and, thereby, a chemical equivalent to natural evolution of NP structure. [10] …”