2-(2-Aminopyrimidin-4-yl)phenol Analogs as PIM Kinase Inhibitors
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PIM kinases, a family of serine/threonine kinases, are major downstream effectors of the Janus kinase/signal transducer and activator of transcription signaling cascade, which drive cell growth, proliferation, and metastasis in solid tumors and hematological cancers. Therefore, PIM kinases are potential targets for anticancer therapies. 2,4-Bis(2-aminopyrimidin-4-yl) phenol is a potential anticancer agent that targets the cyclin-dependent kinase family. As this compound showed submicromolar potency in a PIM-1 kinase assay, we designed 2-(2-aminopyrimidin-4-yl)phenol analogs as PIM kinase inhibitors. Systematic modifications at the 2- and 4- positions of the phenol ring led to the discovery of PIM kinase inhibitor 16, which showed sub-micromolar potency against PIM-2 and double-digit nanomolar potency against PIM-1 and PIM-3 isoforms. Based on molecular docking studies, compound 16 was predicted to bind to the adenosine triphosphate pocket of PIM-1 kinase with two hydrogen bonding interactions and hydrophobic interactions.
Abstract
PIM kinases, a family of serine/threonine kinases, are major downstream effectors of the Janus kinase/signal transducer and activator of transcription signaling cascade, which drive cell growth, proliferation, and metastasis in solid tumors and hematological cancers. Therefore, PIM kinases are potential targets for anticancer therapies. 2,4-Bis(2-aminopyrimidin-4-yl) phenol is a potential anticancer agent that targets the cyclin-dependent kinase family. As this compound showed submicromolar potency in a PIM-1 kinase assay, we designed 2-(2-aminopyrimidin-4-yl)phenol analogs as PIM kinase inhibitors. Systematic modifications at the 2- and 4- positions of the phenol ring led to the discovery of PIM kinase inhibitor 16, which showed sub-micromolar potency against PIM-2 and double-digit nanomolar potency against PIM-1 and PIM-3 isoforms. Based on molecular docking studies, compound 16 was predicted to bind to the adenosine triphosphate pocket of PIM-1 kinase with two hydrogen bonding interactions and hydrophobic interactions.
참고문헌 (20)
- Cao L, "PIM1 kinase promotes cell proliferation, metastasis and tumor growth of lung adenocarcinoma by potentiating the c-MET signaling pathway", Cancer Lett, 444, pp.116~126 (2019)
- Aho TL, "Pim-1 kinase promotes inactivation of the proapoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site", FEBS Lett, 571, pp.43~49 (2004)
- Zhu H-h, "Pim1 overexpression prevents apoptosis in cardiomyocytes after exposure to hypoxia and oxidative stress via upregulating cell autophagy", Cell Physiol Biochem, 49, pp.2138~2150 (2018)
- Isaac M, "The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms", Drug Resistance updates, 14, pp.203~211 (2011)
- Baytel D, "The human Pim-2 proto-oncogene and its testicular expression", Biochim Biophys Acta, 1442, pp.274~285 (1998)
- Kennedy SP, "Preclinical evaluation of a novel triple-acting PIM", PI3K, Oncogene, pp.2020, 39[DOI]
- Arrouchi H, "A review on PIM kinases in tumors", Bioinformation, 15, pp.40~45 (2019)
- Wu J, "PIM Kinases in Multiple Myeloma", Cancers(Basel), 13, pp.4304~ (2021)
- Alnabulsi S, "Pim kinase inhibitors in cancer : Medicinal chemistry insights into their activity and selectivity", Drug Discov Today, 25, pp.2062~2069 (2020)
- Bullock AN, "Structure and substrate specificity of the Pim-1 kinase", J Biol Chem, 280, pp.41675~41682 (2005)
- Bogusz J, "Structural analysis of PIM1 kinase complexes with ATP-competitive inhibitors", Sci Rep, 7, pp.13399~ (2017)
- Seong Y-S, "Characterization of a novel cyclin-dependent kinase 1 inhibitor, BMI-1026", Cancer Res, 63, pp.7384~7391 (2003)
- Niiya F, "Inhibition of cyclindependent kinase 1 induces cytokinesis without chromosome segregation in an ECT2 and MgcRacGAP-dependent manner", J Biol Chem, 280, pp.36502~36509 (2005)
- 서현주, "BMI-1026 treatment can induce SAHF formation by activation of Erk1", 2, 2008, pp.41(7), 523~528[DOI]
- Kim DE, "Cyclin-dependent kinase inhibitor BMI-1026 induces apoptosis by downregulating Mcl-1 (L) and c-FLIP (L) and inactivating p-Akt in human renal carcinoma cells", Int J Mol Sci, 22, pp.4268~ (2021)
- imidazol-2(3H)-one Derivatives as PIM Kinase Inhibitors, "Quantitative Bio-Science", 2022, 17~26, pp.자연과학연구소, 10.22283[DOI]
- Trott O, "AutoDock Vina : improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading", J Comput Chem, 31, pp.455~461 (2010)
- Sanner MF, "Python : a programming language for software integration and development", J Mol Graph Model, 17, pp.57~61 (1999)
- Burger MT, "Structure guided optimization, in vitro activity, and in vivo activity of pan-PIM kinase inhibitors", ACS Med Chem Lett, 4, pp.1193~1197 (2013)
- Zhang M, "CDK inhibitors in cancer therapy, an overview of recent development", Am J Cancer Res, 11, pp.1913~1935 (2021)