Design,synthesis and biological studies of Survivin Dimerization Modulators that prolong mitotic cycle |
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Authors: | Somsundaram N Chettiar James V Cooley In-Hee Park Deepak Bhasin Arnab Chakravarti Pui-Kai Li Chenglong Li Naduparambil Korah Jacob |
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Institution: | 1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Rm 612 Riffe Building, 496 West 12th Avenue, Columbus, OH 43210-1291, United States;2. Department of Radiation Oncology, College of Medicine, The Ohio State University, 366 Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210, United States |
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Abstract: | 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). |
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Keywords: | Survivin LLP3 LLP9 |
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