Biological Activity
nms-1286937 (nms-p937) is a potent and selective inhibitor of polo-like kinase 1 (plk1) with ic50 value of 2 nm [1].plk1 is a serine/threonine protein kinase and plays an important role in the cell cycle control machinery. plk1 is involved in mitotic entry, bipolar mitotic spindle formation, centrosome duplication, transition from metaphase to anaphase, maintenance of genomic stability and cytokinesis [1].nms-1286937 is an orally bioavailable plk1 inhibitor. in cell lines established from solid tumors, leukemias and lymphomas, nms-p937 inhibited tumor cell proliferation. in a2780 cells, nms-p937 caused a g2-m cell-cycle block. in the mitotic phase, nms-p937 induced apoptotic death with misaligned chromosomes and an aberrant number of spindles poles [2]. in human osteosarcoma (os) cell lines, nms-p937 inhibited migration and clonogenic ability of cell lines. in abcb1-overexpressing, doxorubicin (dx)-resistant cell lines, combination of nms-p937 and dx reverted dx-resistance by inhibiting abcb1 transport activity [3].in harlan nu/nu mice, nms-p937 exhibited a good pharmacokinetic profile with low clearance, high auc and cmax, and acceptable oral bioavailability. in mice xenografted with human hct116 colon adenocarcinoma cells, nms-p937 (45 mg/kg) inhibited tumor growth by 83% and reduced body weight by 16% [1].
References
[1]. beria i, bossi rt, brasca mg, et al. nms-p937, a 4,5-dihydro-1h-pyrazolo[4,3-h]quinazoline derivative as potent and selective polo-like kinase 1 inhibitor. bioorg med chem lett, 2011, 21(10): 2969-2974.
[2]. valsasina b, beria i, alli c, et al. nms-p937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. mol cancer ther, 2012, 11(4): 1006-1016.
[3]. sero v, tavanti e, vella s, et al. targeting polo-like kinase 1 by nms-p937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance. invest new drugs, 2014, 32(6): 1167-1180.
