Design, synthesis and biological studies of Survivin Dimerization Modulators that prolong mitotic cycle
Design, synthesis and biological studies of Survivin Dimerization Modulators that prolong mitotic cycle
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DOI：
10.1016/j.bmcl.2013.07.034
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发表时间：
2013-10-01
影响因子：
2.7
通讯作者：
Jacob, Naduparambil Korah
中科院分区：
文献类型：
--
作者：
Chettiar, Somsundaram N.;Cooley, James V.;Jacob, Naduparambil Korah
Survivin是凋亡抑制蛋白（inhibitor of apoptosis protein，IAP）家族的成员，在细胞分裂和抑制凋亡中发挥重要作用。在癌症患者中的几项临床研究表明，生存素水平的升高与疾病的侵袭性以及对放射和化学治疗的抗性相关。存活素是染色体乘客复合物（CPC）的组成部分，其中它通过其二聚化界面与borealin和INCENP结合。因此，假设功能性存活素沿着其二聚体与小分子的界面的破坏抑制癌细胞的增殖并使它们对治疗剂和辐射敏感。最近，一个小分子（Abbott8）被报道在生存素的二聚化界面结合。该化合物的进一步开发是通过沿二聚化界面沿着的分子相互作用的计算建模来完成的，这导致了有前途的存活素二聚化调节剂的设计。两种最有效的生存素调节剂，LLP3和LLP9在50和100 nM之间的浓度下，在增殖的人脐静脉内皮细胞（HUVEC）和前列腺癌细胞（PC 3）中引起有丝分裂进展的延迟和主要的有丝分裂缺陷。(C)2013爱思唯尔有限公司版权所有。
Survivin, a member of the inhibitor of apoptosis protein (IAP) family proteins, has essential roles in cell division and inhibition of apoptosis. Several clinical studies in cancer patients have shown that the elevated levels of survivin correlate with aggressiveness of the disease and resistance to radiation and chemotherapeutic treatments. Survivin is an integral component of chromosomal passenger complex (CPC) where it binds to borealin and INCENP through its dimerization interface. Thus, disruption of functional survivin along its dimer interface with a small molecule is hypothesized to inhibit the proliferation of cancer cells and sensitize them to therapeutic agents and radiation. Recently, a small molecule (Abbott8) was reported to bind at the dimerization interface of survivin. Further development of this compound was accomplished by computational modeling of the molecular interactions along the dimerization interface, which has led to the design of promising survivin dimerization modulators. Two of the most potent survivin modulators, LLP3 and LLP9 at concentrations between 50 and 100 nM, caused delay in mitotic progression and major mitotic defects in proliferating human umbilical vein endothelial cells (HUVEC) and prostate cancer cells (PC3). (C) 2013 Elsevier Ltd. All rights reserved.