Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210-1291, United States.
Bioorg Med Chem Lett. 2013 Oct 1;23(19):5429-33. doi: 10.1016/j.bmcl.2013.07.034. Epub 2013 Jul 24.
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 100nM, caused delay in mitotic progression and major mitotic defects in proliferating human umbilical vein endothelial cells (HUVEC) and prostate cancer cells (PC3).
Survivin 是凋亡抑制蛋白 (IAP) 家族蛋白的成员，在细胞分裂和凋亡抑制中发挥重要作用。癌症患者的几项临床研究表明，Survivin 水平升高与疾病的侵袭性以及对放射和化疗治疗的耐药性相关。Survivin 是染色体乘客复合物 (CPC) 的一个组成部分，在 CPC 中，它通过二聚化界面与 borealin 和 INCENP 结合。因此，假设通过小分子破坏 Survivin 沿着其二聚化界面的功能，可抑制癌细胞的增殖并使它们对治疗剂和辐射敏感。最近，有报道称一种小分子（Abbott8）可结合 Survivin 的二聚化界面。通过对二聚化界面的分子相互作用进行计算建模，进一步开发了这种化合物，从而设计出有前途的 Survivin 二聚化调节剂。两种最有效的 Survivin 调节剂 LLP3 和 LLP9 在 50 到 100nM 的浓度下，导致增殖的人脐静脉内皮细胞 (HUVEC) 和前列腺癌细胞 (PC3) 有丝分裂进程延迟和主要有丝分裂缺陷。
