Marmy-Conus Nelly, Hannan Katherine M, Pearson Richard B
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Locked Bag #1, A'Beckett Street, Melbourne, Vic., Australia.
FEBS Lett. 2002 May 22;519(1-3):135-40. doi: 10.1016/s0014-5793(02)02738-2.
The mitogen-stimulated protein kinase p70(s6k)/p85(s6k) (S6K) plays an essential role in cell proliferation and growth, with inhibitors of the S6K signalling pathway showing promise as anti-tumour therapeutics. Here, we report that the bisindolylmaleimide derivative Ro 31-6045, previously reported to be inactive as a kinase inhibitor, inhibited S6K activity in vivo with an IC50=8 microM. Structure/function analysis using mutant forms of S6K indicates that Ro 31-6045 inhibition is independent of the upstream activator mTOR. Ro 31-6045 will prove useful in elucidating the complex activation mechanism of S6K and its independence from mTOR will allow confirmation of functional data obtained using the mTOR inhibitor rapamycin.
有丝分裂原刺激的蛋白激酶p70(s6k)/p85(s6k)（S6K）在细胞增殖和生长中起关键作用，S6K信号通路抑制剂有望成为抗肿瘤治疗药物。在此，我们报道双吲哚马来酰亚胺衍生物Ro 31-6045，先前报道其作为激酶抑制剂无活性，但在体内能抑制S6K活性，IC50 = 8微摩尔。使用S6K突变体形式进行的结构/功能分析表明，Ro 31-6045的抑制作用不依赖于上游激活剂mTOR。Ro 31-6045将有助于阐明S6K复杂的激活机制，其不依赖于mTOR将有助于确认使用mTOR抑制剂雷帕霉素获得的功能数据。
