The pseudo‐natural product rhonin targets RHOGDI

Akbarzadeh, M., Flegel, J., Patil, S., Shang, E., Narayan, R., Buchholzer, M., Kazemein Jasemi, N.S., Grigalunas, M., Krzyzanowski, A., Abegg, D., Shuster, A., Potowski, M., Karatas, H., Karageorgis, G., Mosaddeghzadeh, N., Zischinsky, M., Merten, C., Golz, C., Brieger, L., Strohmann, C., Antonchick, A.P. ORCID: 0000-0003-0435-9443, Janning, P., Adibekian, A., Goody, R.S., Reza Ahmadian, M., Ziegler, S. and Waldmann, H., 2022. The pseudo‐natural product rhonin targets RHOGDI. Angewandte Chemie International Edition. ISSN 1433-7851

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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.

Item Type: Journal article
Publication Title: Angewandte Chemie International Edition
Creators: Akbarzadeh, M., Flegel, J., Patil, S., Shang, E., Narayan, R., Buchholzer, M., Kazemein Jasemi, N.S., Grigalunas, M., Krzyzanowski, A., Abegg, D., Shuster, A., Potowski, M., Karatas, H., Karageorgis, G., Mosaddeghzadeh, N., Zischinsky, M., Merten, C., Golz, C., Brieger, L., Strohmann, C., Antonchick, A.P., Janning, P., Adibekian, A., Goody, R.S., Reza Ahmadian, M., Ziegler, S. and Waldmann, H.
Publisher: Wiley
Date: 16 February 2022
ISSN: 1433-7851
Identifiers:
NumberType
10.1002/anie.202115193DOI
1524574Other
Rights: © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Divisions: Schools > School of Science and Technology
Record created by: Laura Ward
Date Added: 11 Mar 2022 14:43
Last Modified: 11 Mar 2022 14:43
URI: http://irep.ntu.ac.uk/id/eprint/45866

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