LKB1(AAK1 dual inhibitor) 是一种有效的多激酶抑制剂，对 Pim1/AKK1/MST2/LKB1 的 Kd 值分别为 35 nM/53 nM/75 nM/380 nM，并且还抑制 MPSK1 和 TNIK。
LKB1 is a selective inhibitor of Pim-1 kinase with Kd value of 35 nM [1].
Pim-1 (proto-oncogene serine/threonine-protein kinase) is a proto-oncogene encodes by PIM1 gene and is reported to play an important role in multiple human cancers. Initially, pim-1 is reported to be expressed in spleen, thymus, bone marrow, prostate, oral epithelial cells, etc. Recently, the high expression of pim-1 has been identified in several isolated human cancer cells and been shown to involve in the cell cycle progression, apoptosis, transcriptional activation and many general signal transduction pathways. Therefore, investigation of the inhibition of pim-1 by low molecular weight compounds as a part of anticancer therapeutic strategies needs more attention and progress [2, 3].
参考文献:
1.?? ?Bamborough, P., et al., Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. J Med Chem, 2008. 51(24): p. 7898-914.
2.?? ?Natarajan, K., et al., The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms. Biochem Pharmacol, 2013. 85(4): p. 514-24.
3.?? ?Tsuganezawa, K., et al., A novel Pim-1 kinase inhibitor targeting residues that bind the substrate peptide. J Mol Biol, 2012. 417(3): p. 240-52.
| Kinase experiment [1]: | |
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Binding assays |
Kinases were expressed as fusion proteins to T7 phage. In general, full-length constructs were used for small kinases and catalytic domains for large kinases. T7-kinase-tagged phage strains were mixed with known kinase inhibitors immobilized on streptavidin-coated magnetic beads and with LKB1 (AAK1 dual inhibitor) at a single concentration of 10 μM. LKB1 (AAK1 dual inhibitor) that bind to the kinase ATP site displace the immobilized ligand from the kinase/phage, which is detected using quantitative PCR. The results are reported as the percentage of kinase/phage remaining bound to the ligand/beads, relative to a control (DMSO). High affinity compounds have %control= 0, while weaker binders have higher %control values. Results are reported for screening against 203 human kinases. |
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参考文献: [1]. Bamborough P, Drewry D, Harper G, et al. Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. J Med Chem, 2008, 51(24): 7898-7914. | |
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