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

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 α-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.

GRAPHICAL ABSTRACT

Keywords:

• Phosphonocarboxylate
• Rab geranylgeranyltransferase
• prenylation
• imidazo[1
• 2-a]pyridine
• covalent inhibitors

Acknowledgements

The authors thank Dr. Marek Domin (Boston College) for HRMS of final compounds. The authors thank Dr. Barbara Pacholczyk-Sienicka and Grzegorz Ciepielowski for carrying out NMR experiments. The authors thank Dr. Marzena Jędrzejczak-Krzepkowska for valuable comments on the expression of recombinant proteins and preparing the necessary documentation. We acknowledge CSC − IT Center for Science, Finland, for generous computational resources (O.T.P.: jyy2516 and jyy2585).

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No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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Funding

This work was financially supported by the National Science Centre, Poland: Preludium [2016/23/N/ST5/03230 to J.M.] and Sonata Bis [2014/14/E/ST5/00491 to K.M.B.]. The Academy of Finland is acknowledged for a personal postdoctoral grant for S.N. (decision number 315492). Proteomic measurements were performed at the Proteomics Core Facility, IMol Polish Academy of Sciences utilizing the equipment funded by the ‘Regenerative Mechanisms for Health’ project MAB/2017/2 within the International Research Agendas program of the Foundation for Polish Science, co-financed by the European Union under the European Regional Development Fund.