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Identification of the privileged position in the imidazo[1,2-a]pyridine ring of phosphonocarboxylates for development of Rab geranylgeranyl transferase (RGGT) inhibitors

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Kaźmierczak, A., Kusy, D., Niinivehmas, S., Gmach, J., Joachimiak, Ł., Pentikäinen, O., Gendaszewska-Darmach, E., & Blazewska, K. M. (2017). Identification of the privileged position in the imidazo[1,2-a]pyridine ring of phosphonocarboxylates for development of Rab geranylgeranyl transferase (RGGT) inhibitors. Journal of Medicinal Chemistry, 60(21), 8781-8800. https://doi.org/10.1021/acs.jmedchem.7b00811
Published in
Journal of Medicinal Chemistry
Authors
Kaźmierczak, Aleksandra |
Kusy, Damian |
Niinivehmas, Sanna |
Gmach, Joanna |
Joachimiak, Łukasz |
Pentikäinen, Olli |
Gendaszewska-Darmach, Edyta |
Blazewska, Katarzyna M.
Date
2017
Discipline
Solu- ja molekyylibiologiaNanoscience CenterCell and Molecular BiologyNanoscience Center
Copyright
© 2017 American Chemical Society. This is a final draft version of an article whose final and definitive form has been published by ACS. Published in this repository with the kind permission of the publisher.

 
Members of the Rab GTPase family are master regulators of vesicle trafficking. When disregulated, they are associated with a number of pathological states. The inhibition of RGGT, an enzyme responsible for post-translational geranylgeranylation of Rab GTPases represents one way to control the activity of these proteins. Because the number of molecules modulating RGGT is limited, we combined molecular modeling with biological assays to ascertain how modifications of phosphonocarboxylates, the first reported RGGT inhibitors, rationally improve understanding of their structure–activity relationship. We have identified the privileged position in the core scaffold of the imidazo[1,2-a]pyridine ring, which can be modified without compromising compounds’ potency. Thus modified compounds are micromolar inhibitors of Rab11A prenylation, simultaneously being inactive against Rap1A/Rap1B modification, with the ability to inhibit proliferation of the HeLa cancer cell line. These findings were rationalized by molecular docking, which recognized interaction of phosphonic and carboxylic groups as decisive in phosphonocarboxylate localization in the RGGT binding site. ...
Publisher
American Chemical Society
ISSN Search the Publication Forum
0022-2623
Keywords
rab geranylgeranyl transferase
DOI
https://doi.org/10.1021/acs.jmedchem.7b00811
URI

http://urn.fi/URN:NBN:fi:jyu-201711094175

Publication in research information system

https://converis.jyu.fi/converis/portal/detail/Publication/27277727

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