title: Design, synthesis and biological studies of survivin dimerization modulators that prolong mitotic cycle.
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 100nM, caused delay in mitotic progression and major mitotic defects in proliferating human umbilical vein endothelial cells (HUVEC) and prostate cancer cells (PC3).
authors: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210-1291, United States.
authors: Somsundaram N
authors: SN
authors: Chettiar
authors: James V
authors: JV
authors: Cooley
authors: In-Hee
authors: IH
authors: Park
authors: Deepak
authors: D
authors: Bhasin
authors: Arnab
authors: A
authors: Chakravarti
authors: Pui-Kai
authors: PK
authors: Li
authors: Chenglong
authors: C
authors: Li
authors: Naduparambil Korah
authors: NK
authors: Jacob
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002733:Chlorophenols / Q000737:chemistry* / Q000494:pharmacology*; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D000077022:Survivin; D013997:Time Factors
chemical_list: C587542:4-(3,5-bis(benzyloxy)phenyl)-6-(5-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile; C587543:6-(5-chloro-2-hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002733:Chlorophenols; D051034:Inhibitor of Apoptosis Proteins; D011728:Pyridones; D000077022:Survivin
keywords: LLP3; LLP9; Survivin