The p21-activated kinases (PAKs) have generated significant interest as therapeutic targets in cancer. PAK1 signaling has been shown to be important for regulating cytoskeletal organization and cell migration via both its catalytic activity and protein-protein interactions. FRAX1036, a small molecule pyridopyrimidinone, is a PAK inhibitor. Its biochemical potency (Ki) against PAK1 and PAK2 is 23.3 and 72.4 nM, respectively, with high selectivity against PAK4. Potent cellular inhibition of group I PAK substrate phosphorylation was observed at 2.5 to 5 μM concentrations of FRAX1036 in PAK1-amplified MDA-MB-175 cells. FRAX1036 (5 μM) and docetaxel (0.2 μM) combination treatment for 24 hours of PAK1-amplified lines, MDA-MB-175 and HCC2911, elevated a major apoptotic marker (cleaved PARP) and attenuated a cell cycle regulator (cyclin D1). After 20 hours of treatment with 2.5 μM FRAX1036 for 20 hours, microtubules were disorganized and were not evenly distributed throughout the cytoplasm, between the microtubule organizing center and the periphery. Furthermore, FRAX1036-treated cells completed normal mitoses with the majority of apoptosis occurring during interphase (66.7%)[3].
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