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Small Molecule Inhibitors asAnticancer Agents

Bhasin, Deepak
http://rave.ohiolink.edu/etdc/view?acc_num=osu1305826098

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Pharmacy.
Signal transducer and activator of transcription 3 (STAT3) is one of the downstream signaling proteins for cytokine and growth factor receptors. Receptor activation induces tyrosine phosphorylation leading to dimerization of two STAT monomers by reciprocal phosphotyrosine-SH2 interactions. This dimer translocates into the nucleus where it controls the transcription of several apoptosis and cell cycle-regulatory proteins. STAT3 has been identified to be overexpressed in many different kinds of blood malignancies and solid tumors. Inhibition of STAT3 dimerization stops translocation into the nucleus and induces apoptosis. Several novel small molecules have been synthesized using a structural-based strategy with an aim to specifically inhibit STAT3 dimerization and have been examined for their antiproliferative activity on breast, pancreatic, prostrate and brain cancer. Among the compounds synthesized, LLL-3, LLL-6 and LLL-12 were found to be active against various cancer cell lines. LLL-12 was found to be the most potent analogue among the LLL series of compounds and even more potent than known inhibitors against various cancer cells overexpressing STAT3, and it did not inhibit STAT1. LLL-12 was also found to reduce tumor growth. Arginine methylation is an important post-translational modification which mainly occurs in nuclear proteins and is involved in structural remodeling of chromatin, signal transduction, cellular proliferation, gene transcription, translation, DNA repair, apoptosis, RNA processing, and mRNA splicing. PRMT5 has been shown to catalyze the formation of monomethylargininie (MMA) and symmetric dimethylarginine (sDMA) on a variety of substrates including myelin basic protein (MBP), the Sm ribonucleoproteins, and additional proteins that require symmetric dimethylarginine residues. PRMT5 has been shown to methylate histones H2A, H3 and H4. PRMT5 has been reported to be associated with tumors. PRMT5 overexpression has been documented in multiple non-Hodgkin’s lymphoma cell lines and primary mantle cell lymphoma tumor samples. Molecular docking was used to screen a library of 10,000 compounds to identify 8 potential compounds for biological screening. Subsequent screening identified BLL-1 as our lead compound which was further modified using traditional medicinal chemistry approaches and molecular modeling. BLL-1 was the most potent compound tested on JeKo and Mino cells. Survivin is a 142 amino acid and is the smallest member of the IAP family. Survivin indirectly acts on caspases by associating with cdk4 resulting in release of p21Cip1/Waf1, which interacts with procaspase-3 to suppress Fas mediated cell death.163 Survivin also provides cytoprotection to cells against caspase-independent cell death by inhibiting the AIF pathway. Survivin is present on the mitotic machinery of dividing cells and regulates cell division. Survivin has been shown to be overexpressed in cancer. Lack of Survivin or disruption of the Survivin function would be expected to cause apoptosis in tumor cells. Structural study of compound 2 showed that its binding site is located at the dimerization interface. Compound 2 was modified with an aim to target the Survivin binding site. LLP-3 was found to be active at 50 μm against various cancer cell lines. LLP-3 also delayed mitosis and cells appeared to lose viability after being exposed to LLP-3 for 48 hours.
Pui-Kai Li (Advisor)
James Fuchs (Committee Member)
Chenglong Li (Committee Member)
368 p.
Chemistry; Pharmacy Sciences
STAT3; PRMT5; Survivin inhibitors

Recommended Citations

Citations

  • Bhasin, D. (2011). Small Molecule Inhibitors asAnticancer Agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305826098

    APA Style (7th edition)

  • Bhasin, Deepak. Small Molecule Inhibitors asAnticancer Agents. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1305826098.

    MLA Style (8th edition)

  • Bhasin, Deepak. "Small Molecule Inhibitors asAnticancer Agents." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305826098

    Chicago Manual of Style (17th edition)

osu1305826098
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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.