Discovery of novel pyrazolo[3, 4-b]pyridine scaffold-based derivatives as potential PIM-1 kinase inhibitors in breast cancer MCF-7 cells. Issue 24 (15th December 2020)

• Record Type: Journal Article
• Authors: Nafie, Mohamed S.; Amer, Atef M.; Mohamed, Anaiat K.; Tantawy, Eman S.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 24(2020)
• Publication Date: 2020-12-15
• Subjects: Apoptosis -- Breast cancer -- Docking -- PIM-1 kinase -- Pyrazolo-pyridines; PIM-1 Proto-oncogene serine/threonine -- IC50 kinase - half minimal inhibitor concentration -- 5-FU 5-fluorouracil -- Ct cycle threshold -- m.p melting point -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- MCF-7 MDA-MB-231, human breast cancer cell lines -- MCF-10A normal breast cell line -- ER estrogen dependent -- mL/µl millilitre/microliter -- SEM standard error of mean -- PI propidium iodide -- Pre G1 G0/G1, S, G2/M, cell cycle phases; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115828
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel pyrazolo[3, 4- b ]pyridine scaffold-based derivatives were synthesized and characterized. Both Compound 17 and 19 were found to be potent and selective against MCF-7 cells through apoptosis-inducing activity. Both compounds 17 and 19 were good inhibitors for PIM-1 kinase in both enzymatic, RT-PCR, and in silico assays. Abstract: Pim-1 kinase targeted recently has proved an essential goal of breast cancer therapy. We report the design, synthesis with full characterization analysis of pyrazolo[3, 4- b ]pyridine scaffold-based derivatives targeting Pim-1 kinase as anti-breast cancer agents. All the newly synthesized compounds were screened for their in vitro cytotoxic activity against two breast cancer cell lines MCF-7 and MDA-MB-231, and non-cancerous MCF-10A cells. Four derivatives notably, 17 and 19 exhibited a remarkable cytotoxic activity with IC50 values 5.98 and 5.61 µM against MCF-7 (ERα-dependent) cells in a selective way, as they weren't active against MDA-MB-231 (non-ERα-dependent) and safe against MCF-10A. The most active compounds through in vitro screening were subjected to PIM-1 kinase to elucidate the Pim-1 kinase inhibitory activity as the mechanistic mode of action. Among the tested derivatives, Compounds 17 and 19 showed the highest inhibitory activity with IC50 values 43 and 26 nM, respectively, compared to the 5-FU with IC50 value 17 nM. Moreover, apoptotic investigation through flow cytometry and gene expression analysis of the apoptosis-related genes for the most active compound 19 against MCF-7. It was found that compound 19 induced apoptotic MCF-7 cell death by cell cycle arrest at G2/M phase and by elevation the expression of pro-apoptotic genes and inhibition of anti-apoptotic genes expression. Finally, the PIM-1 inhibition activities for compounds 17 and 19 were in accordance with the molecular docking study that revealed good interaction with the Pim-1 kinase active site.