SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest.
SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest.
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DOI：
10.1371/journal.pone.0119346
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wang QJ
中科院分区：
文献类型：
--
作者：
Tandon M;Salamoun JM;Carder EJ;Farber E;Xu S;Deng F;Tang H;Wipf P;Wang QJ
蛋白激酶D(PKD)参与肿瘤发生、发展的多个方面，是抗癌治疗发展的一个新的分子靶点。尽管最近在开发有效和选择性的PKD小分子抑制剂方面取得了进展，但体内活性PKD抑制剂的可用性仍然很少。在这项研究中，我们描述了一种新的PKD小分子抑制剂SD-208的发现，从靶向的激酶抑制剂文库中筛选，并合成了一系列类似物来探索与PKD1的构效关系(SAR)。SD-208表现出较窄的SAR谱，是一种ATP竞争性的PAN-PKD抑制剂，具有低纳摩尔效力，并具有细胞活性。SD-208靶向抑制PKD可有效抑制细胞增殖，这种作用可被过表达的PKD1或PKD3逆转。SD-208还阻止了前列腺癌细胞的存活和侵袭，并将细胞停滞在细胞周期的G2/M期。在机制上，SD-208诱导的G2/M期停滞伴随着DU145和PC3细胞中p21水平的增加以及DU145细胞中CDc2和CDc25C的磷酸化水平的增加。最重要的是，SD-208连续给药24天可显著抑制PC3裸鼠皮下移植瘤的生长，并伴随着细胞增殖抑制、细胞凋亡增加以及PKD标志物Survivin和Bclxl表达的降低。我们的研究已经确定SD-208是一种新的有效的PKD小分子抑制剂，显示了靶向抑制PKD用于前列腺癌治疗的潜力。
Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment.
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影响因子：
11.2
作者：
Mohammad KS;Javelaud D;Fournier PG;Niewolna M;McKenna CR;Peng XH;Duong V;Dunn LK;Mauviel A;Guise TA
通讯作者：
Guise TA
影响因子：
8
作者：
Agarwal, C;Singh, RP;Agarwal, R
通讯作者：
Agarwal, R
影响因子：
7.3
作者：
Meredith, Erik L.;Beattie, Kimberly;Monovich, Lauren G.
通讯作者：
Monovich, Lauren G.
影响因子：
4.8
作者：
Sturany, S;Van Lint, J;Seufferlein, T
通讯作者：
Seufferlein, T
影响因子：
4.2
作者：
Bravo-Altamirano, Karla;George, Kara M.;Frantz, Marie-Celine;LaValle, Courtney R.;Tandon, Manuj;Leimgruber, Stephanie;Sharlow, Elizabeth R.;Lazo, John S.;Wang, Q. Jane;Wipf, Peter
通讯作者：
Wipf, Peter