in vitro and in silico Studies of Interaction of Synthetic 2,6,9-Trisubstituted Purine Kinase Inhibitors BPA-302, BP-21 and BP-117 With Liver Drug-Metabolizing Cytochromes P450

0541026 - ÚEB 2022 RIV CZ eng J - Journal Article
Spicakova, A. - Kraus, Petr - Gucký, Tomáš - Kryštof, Vladimír - Strnad, Miroslav - Bazgier, V. - Otyepka, M. - Kubickova, V. - Poruba, M. - Rácová, Z. - Zapletalová, I. - Anzenbacher, P.
in vitro and in silico Studies of Interaction of Synthetic 2,6,9-Trisubstituted Purine Kinase Inhibitors BPA-302, BP-21 and BP-117 With Liver Drug-Metabolizing Cytochromes P450.
Physiological Research. Roč. 69, SEP (2020), s. 627-636. ISSN 0862-8408. E-ISSN 1802-9973
R&D Projects: GA MZd(CZ) NV17-28231A
Institutional support: RVO:61389030
Keywords : r-roscovitine * cell-cycle * cancer * series * Cytochrome P450 inhibition * High performance liquid chromatography * Cyclin-dependent kinase inhibitor * FLT3-ITD inhibitor * Drug metabolism
OECD category: Organic chemistry
Impact factor: 1.881, year: 2020
Method of publishing: Open access
https://www.biomed.cas.cz/physiolres/pdf/2020/69_S627.pdf

An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA-302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 mu mol.l(-1)). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.
Permanent Link: http://hdl.handle.net/11104/0318600