A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase
Tekijät: Malolepsza Joanna, Marchwicka Aleksandra, Serwa Remigiusz A., Niinivehmas Sanna P., Pentikäinen Olli T., Gendaszewska-Darmach Edyta, Blazewska Katarzyna M.
Kustantaja: TAYLOR & FRANCIS LTD
Julkaisuvuosi: 2022
Journal: Journal of Enzyme Inhibition and Medicinal Chemistry
Tietokannassa oleva lehden nimi: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Lehden akronyymi: J ENZYM INHIB MED CH
Vuosikerta: 37
Numero: 1
Aloitussivu: 940
Lopetussivu: 951
Sivujen määrä: 12
ISSN: 1475-6366
eISSN: 1475-6374
DOI: https://doi.org/10.1080/14756366.2022.2053525
Verkko-osoite: https://doi.org/10.1080/14756366.2022.2053525
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/175054974
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
