The search for potential inhibitors of protein kinase Pim-1 among new amides of 1,2,4-triazolo[4,3-a]pyridine-3-metanamin with the 1,2,4-oxadiazol cycle in position 7 and 8

• Published in: Z͡h︡urnal orhanichnoï ta farmat͡s︡evtychnoï khimiï Vol. 17; no. 3(67); pp. 5 - 14
• Main Authors: Karpina, V. R., Kovalenko, S. M., Zaremba, O. V., Silin, O. V., Ivanov, V. V., Kovalenko, S. S., Langer, T.
• Format: Journal Article
• Language: English
• Published: National University of Pharmacy (Kharkiv) 01.09.2019
• Subjects: antitumor activity; oxadiazole; pharmacophore model; pim-1 protein kinase; triazolopyridine; virtual screening
• ISSN: 2308-8303; 2518-1548
• DOI: 10.24959/ophcj.19.174807

The Pim-1 enzyme from the serine/threonine protein kinase family is a likely target for the targeted therapy of tumors of hematopoietic and lymphoid tissues. Triazolopyridine is an universal scaffold upon which international scientific programs have been launched to develop potential anticancer agents. Aim. To create a pharmacophore model to find new potential Pim-1 inhibitors; conduct a virtual screening of a simulated base of new 1,2,4-triazolo[4,3-a]pyridine derivatives; develop a method for the synthesis of 1,2,4-triazolo[4,3-a]pyridine-3-methanamines with the 1,2,4-isoxadiazole cycle. Results and discussion. In this study, a ligand-based pharmacophore model for Pim-1 inhibitors was constructed and validated. A virtual screening of the library with 912 compounds resulted in a hit list of 175 compounds. For the synthesis, 15 compounds were selected with the highest pharmacophore-fit score. 15 compounds were synthesized as potential inhibitors of Pim-1 kinase. Experimental part. The synthetic approach has been developed, and systematic series of new amides of (7-(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine and (8-(1,2,4-oxadiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine have been synthesized. Conclusions. The compounds obtained are potential inhibitors of Pim-1 kinase. Further studies will focus on the determination of the antitumor activity of the compounds synthesized by in vitro and in vivo methods.