Control of angiogenesis is an attractive possibility for controlling cancer. Consequently, antiangiogenic compounds have considerable potential as therapeutic agents. To date, only a few of the more than fifty in vivo-active antiangiogenics are small molecules. Yet low molecular weight agents are more desirable from a therapeutic vantage point. Our preliminary studies are significant because they show that it is quite likely we will be able to produce small molecule antiangiogenic agents. Namely, we have i) discovered a novel antiangiogenic antitumor peptide, betapep-25, that inhibits tumor growth in mice, ii) identified key structural elements through SAR studies of betapep-25, and iii) rationally designed and prepared a structurally simpler dibenzofuran-based analog of betapep-25 that maintains the essential in vitro biological activity of betapep-25. This significant body of data provides support and momentum for the planned studies that have the following aims:
Aim 1 :identify the key structural elements in the dibenzofuran analog that promotes antiangiogenic activity and then to enhance this activity.
Aim 2 : study the in vivo antiangiogenic and anti-tumor effectivenes and pharmacokinetic properties of the most potent analogs from Aim 1.
Aim 3 : enhance the bioavailability of the most potent analog from Aim 2.
Aim 4 : investigate use of combined antiangiogenic therapy and chemotherapy against tumors in vivo. This application presents a comprehensive and integrated plan that will enable us to capitalize on the exciting discovery of the antiangiogenic antitumor properties of betapep-25.
|Rauthu, Subhash R; Shiao, Tze Chieh; André, Sabine et al. (2015) Defining the potential of aglycone modifications for affinity/selectivity enhancement against medically relevant lectins: synthesis, activity screening, and HSQC-based NMR analysis. Chembiochem 16:126-39|
|Ippel, Hans; Miller, Michelle C; Berbís, Manuel Alvaro et al. (2015) (1)H, (13)C, and (15)N backbone and side-chain chemical shift assignments for the 36 proline-containing, full length 29 kDa human chimera-type galectin-3. Biomol NMR Assign 9:59-63|
|Dings, Ruud P M; Kumar, Nigam; Miller, Michelle C et al. (2013) Structure-based optimization of angiostatic agent 6DBF7, an allosteric antagonist of galectin-1. J Pharmacol Exp Ther 344:589-99|
|Ermakova, Elena; Miller, Michelle C; Nesmelova, Irina V et al. (2013) Lactose binding to human galectin-7 (p53-induced gene 1) induces long-range effects through the protein resulting in increased dimer stability and evidence for positive cooperativity. Glycobiology 23:508-23|
|Dings, Ruud P M; Levine, Joseph I; Brown, Susan G et al. (2013) Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer. Invest New Drugs 31:1142-50|
|Kumar, Nigam; Ippel, Hans; Weber, Christian et al. (2013) Protein lysine-N? alkylation and O-phosphorylation mediated by DTT-generated reactive oxygen species. Protein Sci 22:327-46|
|Nesmelova, Irina V; Berbís, Manuel Álvaro; Miller, Michelle C et al. (2012) 1H, 13C, and 15N backbone and side-chain chemical shift assignments for the 31 kDa human galectin-7 (p53-induced gene 1) homodimer, a pro-apoptotic lectin. Biomol NMR Assign 6:127-9|
|Miller, Michelle C; Klyosov, Anatole A; Mayo, Kevin H (2012) Structural features for ?-galactomannan binding to galectin-1. Glycobiology 22:543-51|
|Dings, Ruud P M; Miller, Michelle C; Nesmelova, Irina et al. (2012) Antitumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding. J Med Chem 55:5121-9|
|Dings, Ruud P M; Vang, Kieng B; Castermans, Karolien et al. (2011) Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer. Clin Cancer Res 17:3134-45|
Showing the most recent 10 out of 33 publications