Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase - UTU Research Portal

A1 Refereed original research article in a scientific journal

Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase

Authors: Malolepsza Joanna, Marchwicka Aleksandra, Serwa Remigiusz A., Niinivehmas Sanna P., Pentikäinen Olli T., Gendaszewska-Darmach Edyta, Blazewska Katarzyna M.

Publisher: TAYLOR & FRANCIS LTD

Publication year: 2022

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Journal name in source: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Journal acronym: J ENZYM INHIB MED CH

Volume: 37

Issue: 1

First page : 940

Last page: 951

Number of pages: 12

ISSN: 1475-6366

eISSN: 1475-6374

DOI: https://doi.org/10.1080/14756366.2022.2053525

Web address : https://doi.org/10.1080/14756366.2022.2053525

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/175054974

Abstract

Rab geranylgeranyltransferase (GGTase-II, RGGT) catalyses the post-translational modification of eukaryotic Rab GTPases, proteins implicated in several pathologies, including cancer, diabetes, neurodegenerative, and infectious diseases. Thus, RGGT inhibitors are believed to be a potential platform for the development of drugs and tools for studying processes related to the abnormal activity of Rab GTPases. Here, a series of new alpha-phosphonocarboxylates have been prepared in the first attempt of rational design of covalent inhibitors of RGGT derived from non-covalent inhibitors. These compounds were equipped with electrophilic groups capable of binding cysteines, which are present in the catalytic cavity of RGGT. A few of these analogues have shown micromolar activity against RGGT, which correlated with their ability to inhibit the proliferation of the HeLa cancer cell line. The proposed mechanism of this inhibitory activity was rationalised by molecular docking and mass spectrometric measurements, supported by stability and reactivity studies.

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Rational design optimization and biological evaluation of novel Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase.pdf