From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-pliosphoinositide-dependent protein kinase-1 inhibitors (Publication with Expression of Concern. See vol. 79, pg. 1716, 2019)
From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-pliosphoinositide-dependent protein kinase-1 inhibitors (Publication with Expression of Concern. See vol. 79, pg. 1716, 2019)
复制标题
DOI：
10.1158/0008-5472.can-03-4063
复制
发表时间：
2004-06-15
期刊：
影响因子：
11.2
通讯作者：
Chen, CS
中科院分区：
文献类型：
--
作者：
Zhu, JX;Huang, JW;Chen, CS
通过抑制3-磷酸肌醇依赖性激酶-1（PDK-1）阻断Akt活化是塞来昔布介导细胞凋亡的主要信号传导机制。然而，塞来昔布是一种弱的PDK-1抑制剂（IC 50，48 μ m），需要至少30 μ m才能在体外对肿瘤细胞的生长表现出可辨别的作用。在这里，我们报告了塞来昔布的结构优化，以开发在酶抑制和生长抑制方面具有更大效力的PDK-1抑制剂。塞来昔布对PDK-1的抑制动力学表明，塞来昔布衍生物通过与ATP竞争结合来抑制PDK-1，这一机制与许多激酶抑制剂相似。结构-活性分析与分子建模一起用于产生化合物，所述化合物被测试其抑制PDK-1激酶活性和诱导PC-3前列腺癌细胞凋亡的效力。将有效化合物对接到PDK-1的ATP结合位点中进行先导物优化，得到两种化合物OSU-03012和OSU-03013，其在PDK-1抑制和细胞凋亡诱导中的IC 50值在低μ m范围内。PC-3细胞暴露于这些试剂导致Akt去磷酸化和抑制p70 S6激酶活性。此外，组成型活性形式的PDK-1和Akt的过表达部分保护OSU-03012诱导的细胞凋亡。在一组60个细胞系中进行的筛选和在PC-3细胞中进行的更广泛的测试表明，两种药物的总生长抑制的平均浓度相似于3 μ M。考虑到PDK-1/Akt信号在促进肿瘤发生中的保守作用，这些塞来昔布类似物对于癌症预防和治疗具有翻译相关性。
The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC50, 48 mum), requiring at least 30 mum to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC50 values in PDK-1 inhibition and apoptosis induction in the low mum range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was similar to3 mum for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.