Design and synthesis of a cell-permeable, drug-like small molecule inhibitor targeting the polo-box domain of polo-like kinase 1.
Design and synthesis of a cell-permeable, drug-like small molecule inhibitor targeting the polo-box domain of polo-like kinase 1.
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DOI：
10.1371/journal.pone.0107432
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Bang JK
中科院分区：
文献类型：
--
作者：
Srinivasrao G;Park JE;Kim S;Ahn M;Cheong C;Nam KY;Gunasekaran P;Hwang E;Kim NH;Shin SY;Lee KS;Ryu E;Bang JK
Polo样激酶-1（Plk 1）在细胞增殖中起重要作用，抑制Plk 1被认为是特异性抑制药物的潜在靶点。几个研究小组已经确定了基于肽的抑制剂，其靶向Plk 1的polo-box结构域（PBD），并在体外测定中以高亲和力与蛋白质结合。然而，肽的蛋白水解抗性和细胞渗透性不足阻碍了这些基于肽的抑制剂开发成新的治疗化合物。为了克服肽类抑制剂的缺点，我们设计并合成了小分子抑制剂。在这些分子中，bg-34表现出与Plk 1-PBD的高结合亲和力，并且它可以以其未修饰的形式穿过细胞膜。此外，bg-34依赖性抑制Plk 1-PBD足以诱导HeLa细胞凋亡。此外，对Plk 1-PBD与bg-34复合物进行的建模研究表明，bg-34可以与Plk 1-PBD有效地相互作用。我们证明，分子bg-34是一个潜在的候选药物，具有抗Plk 1-PBD活性，并具有良好的特性，高细胞渗透性和稳定性。我们还确定了bg-34通过在与PEG化4j肽相同的浓度下抑制HeLa细胞中的Plk 1-PBD来诱导凋亡性细胞死亡，在体外测定中，PEG化4j肽可以比bg-34更有效地抑制Plk 1-PBD活性1000倍。本研究为设计和开发具有更好治疗活性的类药物小分子Plk 1-PBD抑制剂奠定了基础。
Polo-like kinase-1 (Plk1) plays a crucial role in cell proliferation and the inhibition of Plk1 has been considered as a potential target for specific inhibitory drugs in anti-cancer therapy. Several research groups have identified peptide-based inhibitors that target the polo-box domain (PBD) of Plk1 and bind to the protein with high affinity in in vitro assays. However, inadequate proteolytic resistance and cell permeability of the peptides hinder the development of these peptide-based inhibitors into novel therapeutic compounds. In order to overcome the shortcomings of peptide-based inhibitors, we designed and synthesized small molecule inhibitors. Among these molecules, bg-34 exhibited a high binding affinity for Plk1-PBD and it could cross the cell membrane in its unmodified form. Furthermore, bg-34-dependent inhibition of Plk1-PBD was sufficient for inducing apoptosis in HeLa cells. Moreover, modeling studies performed on Plk1-PBD in complex with bg-34 revealed that bg-34 can interact effectively with Plk1-PBD. We demonstrated that the molecule bg-34 is a potential drug candidate that exhibits anti-Plk1-PBD activity and possesses the favorable characteristics of high cell permeability and stability. We also determined that bg-34 induced apoptotic cell death by inhibiting Plk1-PBD in HeLa cells at the same concentration as PEGylated 4j peptide, which can inhibit Plk1-PBD activity 1000 times more effectively than bg-34 can in in vitro assays. This study may help to design and develop drug-like small molecule as Plk1-PBD inhibitor for better therapeutic activity.
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影响因子：
4
作者：
Liu F;Park JE;Qian WJ;Lim D;Scharow A;Berg T;Yaffe MB;Lee KS;Burke TR Jr
通讯作者：
Burke TR Jr
靶向polo样激酶1的polo盒结构域的环状肽抑制剂的开发。
影响因子：
3.5
作者：
Murugan RN;Park JE;Lim D;Ahn M;Cheong C;Kwon T;Nam KY;Choi SH;Kim BY;Yoon DY;Yaffe MB;Yu DY;Lee KS;Bang JK
通讯作者：
Bang JK
影响因子：
3.7
作者：
Murugan RN;Ahn M;Lee WC;Kim HY;Song JH;Cheong C;Hwang E;Seo JH;Shin SY;Choi SH;Park JE;Bang JK
通讯作者：
Bang JK
影响因子：
16.6
作者：
Sledz, Pawel;Stubbs, Christopher J.;Lang, Steffen;Yang, Yong-Qing;McKenzie, Grahame J.;Venkitaraman, Ashok R.;Hyvoenen, Marko;Abell, Chris
通讯作者：
Abell, Chris
影响因子：
14.8
作者：
Liu, Fa;Park, Jung-Eun;Qian, Wen-Jian;Lim, Dan;Graeber, Martin;Berg, Thorsten;Yaffe, Michael B.;Lee, Kyung S.;Burke, Terrence R., Jr.
通讯作者：
Burke, Terrence R., Jr.