Imparting Aromaticity to 2-pyridone Derivatives by -alkylation Resulted in New Competitive and Non-competitive PIM-1 Kinase Inhibitors with Caspase-activated Apoptosis

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2024 Jan 17

PMID 38230430

Authors

Marwa E Abdelaziz

Mostafa M M El-Miligy

Salwa M Fahmy

Marwa M Abu-Serie

Aly A Hazzaa

Mona A Mahran

Affiliations

Soon will be listed here.

Abstract

New aromatic -alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. and showed potent anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, and induced apoptosis in the four tested cancer cell lines with high percentage. In addition, and significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, and showed potent PIM-1 kinase inhibitory activity with IC = 0.110, 0.095 µM, respectively. Kinetic studies indicated that and were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that and could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

References

Schenone S, Tintori C, Botta M . Using insights into Pim1 structure to design new anticancer drugs. Curr Pharm Des. 2010; 16(35):3964-78. DOI: 10.2174/138161210794454996. View

Brown A . A new software for carrying out one-way ANOVA post hoc tests. Comput Methods Programs Biomed. 2005; 79(1):89-95. DOI: 10.1016/j.cmpb.2005.02.007. View

Puente-Moncada N, Costales P, Antolin I, Nunez L, Oro P, Hermosilla M . Inhibition of FLT3 and PIM Kinases by EC-70124 Exerts Potent Activity in Preclinical Models of Acute Myeloid Leukemia. Mol Cancer Ther. 2018; 17(3):614-624. DOI: 10.1158/1535-7163.MCT-17-0530. View

Wang B, Huang C, Liu L, Cheng F, Wei Y, Lin Y . Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2. Front Pharmacol. 2021; 12:614673. PMC: 8276059. DOI: 10.3389/fphar.2021.614673. View

Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65(1-2):55-63. DOI: 10.1016/0022-1759(83)90303-4. View

Sotriffer C . Accounting for induced-fit effects in docking: what is possible and what is not?. Curr Top Med Chem. 2010; 11(2):179-91. DOI: 10.2174/156802611794863544. View

Morwick T . Pim kinase inhibitors: a survey of the patent literature. Expert Opin Ther Pat. 2010; 20(2):193-212. DOI: 10.1517/13543770903496442. View

Zhang M, Liu T, Sun H, Weng W, Zhang Q, Liu C . Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect. Cancer Sci. 2018; 109(5):1468-1479. PMC: 5980151. DOI: 10.1111/cas.13562. View

Ogawa N, Yuki H, Tanaka A . Insights from Pim1 structure for anti-cancer drug design. Expert Opin Drug Discov. 2012; 7(12):1177-92. DOI: 10.1517/17460441.2012.727394. View

10.

Li J, Hu X, Loveland B, Xing P . Pim-1 expression and monoclonal antibody targeting in human leukemia cell lines. Exp Hematol. 2009; 37(11):1284-94. DOI: 10.1016/j.exphem.2009.08.002. View

11.

Cheney I, Yan S, Appleby T, Walker H, Vo T, Yao N . Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase. Bioorg Med Chem Lett. 2007; 17(6):1679-83. DOI: 10.1016/j.bmcl.2006.12.086. View

12.

Arrouchi H, Lakhlili W, Ibrahimi A . A review on PIM kinases in tumors. Bioinformation. 2019; 15(1):40-45. PMC: 6651028. DOI: 10.6026/97320630015040. View

13.

Walhekar V, Bagul C, Kumar D, Muthal A, Achaiah G, Kulkarni R . Topical advances in PIM kinases and their inhibitors: Medicinal chemistry perspectives. Biochim Biophys Acta Rev Cancer. 2022; 1877(3):188725. DOI: 10.1016/j.bbcan.2022.188725. View

14.

Chen J, Kobayashi M, Darmanin S, Qiao Y, Gully C, Zhao R . Hypoxia-mediated up-regulation of Pim-1 contributes to solid tumor formation. Am J Pathol. 2009; 175(1):400-11. PMC: 2708825. DOI: 10.2353/ajpath.2009.080972. View

15.

Nirwan S, Chahal V, Kakkar R . A comparative study of different docking methodologies to assess the protein-ligand interaction for the MurB enzyme. J Biomol Struct Dyn. 2021; 40(21):11229-11238. DOI: 10.1080/07391102.2021.1957019. View

16.

Lee S, Han B, Cho J, Choi J, Lee J, Song H . Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. PLoS One. 2013; 8(7):e70358. PMC: 3729456. DOI: 10.1371/journal.pone.0070358. View

17.

Hassan A, Hafez T, Osman S . Synthesis, Characterization, and Cytotoxicity of Some New 5-Aminopyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives. Sci Pharm. 2016; 83(1):27-39. PMC: 4727791. DOI: 10.3797/scipharm.1409-14. View

18.

Ye C, Zhang C, Huang H, Yang B, Xiao G, Kong D . The Natural Compound Myricetin Effectively Represses the Malignant Progression of Prostate Cancer by Inhibiting PIM1 and Disrupting the PIM1/CXCR4 Interaction. Cell Physiol Biochem. 2018; 48(3):1230-1244. DOI: 10.1159/000492009. View

19.

Letizia Barreca M, Iraci N, De Luca L, Chimirri A . Induced-fit docking approach provides insight into the binding mode and mechanism of action of HIV-1 integrase inhibitors. ChemMedChem. 2009; 4(9):1446-56. DOI: 10.1002/cmdc.200900166. View

20.

Stafman L, Mruthyunjayappa S, Waters A, Garner E, Aye J, Stewart J . Targeting PIM kinase as a therapeutic strategy in human hepatoblastoma. Oncotarget. 2018; 9(32):22665-22679. PMC: 5978256. DOI: 10.18632/oncotarget.25205. View