Discovery of Orally Active Nonpeptide Vitronectin Receptor Antagonists Based on a 2-Benzazepine Gly-Asp Mimetic

Miller, William H.; Alberts, Doreen; Bhatnagar, Pradip K.; Bondinell, William E.; Callahan, James F.; Calvo, Raul R.; Cousins, Russell D.; Erhard, Karl F.; Heerding, Dirk A.; Keenan, Richard M.; Kwon, Chet; Manley, Peter J.; Newlander, Kenneth A.; Ross, Stephen T.; Samanen, James M.; Uzinskas, Irene N.; Venslavsky, Joseph W.; Yuan, Catherine C.K.; Haltiwanger, R. C.; Gowen, Maxine; Hwang, Shing Mei; James, Ian E.; Lark, Michael W.; Rieman, David J.; Stroup, George B.; Azzarano, Leonard M.; Salyers, Kevin L.; Smith, Brian R.; Ward, Keith W.; Johanson, Kyung; Huffman, William F.

doi:10.1021/jm990446u

Cited by 114 publications

(56 citation statements)

References 28 publications

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“…It has a high affinity for a v b 3 (K i ¼1.2 nmol/l), much lower affinity for a 5 b 1 (K i ¼110 nmol/l) and a very low affinity for a IIb b 3 (K i ¼3800 nmol/l). Moreover, SB-273005 has an IC 50 > 200 lmol/l for inhibition of human platelet aggregation [22]. The mouse/human chimeric c7E3 Fab (Abciximab, ReoPro Ò ) which binds to both human platelet a IIb b 3 and a v b 3 integrins with equivalent affinity [23] was from Lilly laboratories.…”

Section: Integrin Inhibitorsmentioning

confidence: 99%

Breast adenocarcinoma cell adhesion to the vascular subendothelium in whole blood and under flow conditions: Effects of α v β 3 and α IIb β 3 antagonists

Gomes

Vassy

Lebos

et al. 2004

Clin Exp Metastasis

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Tumour cell adhesion to vascular extracellular matrix (ECM), an important step of metastatic progression, is promoted by platelets. The aim of our study was to investigate, in whole blood under venous and arterial shear conditions, the respective role of tumour cell a v b 3 and platelet a IIb b 3 integrins in MDA-MB-231 breast adenocarcinoma cell adhesion to human umbilical vein endothelial cell ECM. For that purpose, blood containing MDA-MB-231 cells was incubated with non-peptide antagonists specific for platelet a IIb b 3 (lamifiban) or tumour cell a v b 3 (SB-273005). At 300 s )1 , each antagonist used alone did not modify tumour cell adhesion, whereas, at 1500 s )1 , tumour cell adhesion was decreased by 25% in presence of lamifiban indicating a role of platelet a IIb b 3 at higher shear rate. However, a combination of SB-273005 and lamifiban, or c7E3 Fab (a potent inhibitor of both a IIb b 3 and a v b 3 ) inhibited tumour cell adhesion by 40-45%, at either shear rate applied, indicating a cooperation between these two integrins in MDA-MB-231 cell adhesion to ECM, as well as the participation of other adhesive receptors on tumour cells and/or platelets. Thus, efficient anti-metastatic therapy should target multiple receptors on tumour cells and platelets. Abbreviations: BSA -bovine serum albumin; DMEM -dulbecco modified eagle medium; ECM -extracellular matrix; EDTA -ethylenediaminetetraacetic acid; FITC -fluorescein isothiocyanate; HEPES -N-[2-hydroxyethyl]piperazine-N¢-[2-ethanesulfonic acid]; HUVEC -human umbilical vein endothelial cells; IgG -immunoglobulin;

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Section: Integrin Inhibitorsmentioning

confidence: 99%

Breast adenocarcinoma cell adhesion to the vascular subendothelium in whole blood and under flow conditions: Effects of α v β 3 and α IIb β 3 antagonists

Gomes

Vassy

Lebos

et al. 2004

Clin Exp Metastasis

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“…24 These include Vitaxin, a humanized form of mouse anti-human a v b 3 mAb LM609, [25][26][27] a fully human anti-human a v mAb CNTO95, 28 cyclic RGD peptides, 29 and synthetic small molecule RGD mimetics. 30,31 We have developed a chemically programmed antibody approach that is unique, wherein small synthetic molecules and catalytic mAb form a reversible covalent bond that results in the reprogramming of the specificity of the antibody both in vitro and in vivo. 32 The chemically programmed antibody (cp38C2) is prepared by covalently linking a small synthetic molecule, RGD mimetic SCS-873, which binds specifically to integrins a v b 3 and a v b 5 , to aldolase mAb 38C2 (Fig.…”

mentioning

confidence: 99%

Small molecule drug activity in melanoma models may be dramatically enhanced with an antibody effector

Popkov

Rader

González

et al. 2006

Intl Journal of Cancer

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Monoclonal antibody (mAb) 38C2 belongs to a group of catalytic antibodies that were generated by reactive immunization and contains a reactive lysine. 38C2 catalyzes aldol and retro-aldol reactions, using an enamine mechanism, and mechanistically mimics natural aldolase enzymes. In addition, mAb 38C2 can be redirected to target integrins a v b 3 and a v b 5 through the formation of a covalent bond between a b-diketone derivative of an arginine-glycine-aspartic acid (RGD) peptidomimetic and the reactive lysine residue in the antibody combining site to provide the chemically programmed mAb cp38C2. In this study, we investigated the potential of enhancing the activity of receptor-binding small molecule drug (SCS-873) through antibody conjugation. Using a M21 human melanoma xenograft model in nude mice, cp38C2 inhibited the growth of the tumor by~81%. The chemically programmed antibody was shown to be highly active at a low concentration while SCS-873 alone was ineffective even at dosages~1,000-fold higher than those used for the chemically programmed antibody. In vitro programming of the catalytic antibody was shown to be as effective as in vivo programming. In an experimental metastasis assay, treatment with mAb cp38C2 significantly prolonged overall survival of tumor-bearing severe combined immuno-deficient (SCID) mice when compared to treatment with unprogrammed mAb 38C2, SCS-873 alone or the integrin-specific monoclonal antibody LM609. In vitro, cp38C2 inhibited human and mouse endothelial and human melanoma cell adhesion, migration and invasion. Additionally, cp38C2 inhibited human and mouse endothelial cell proliferation and was active in complement-dependent cytotoxicity assays. These studies establish the potential of chemically programmed monoclonal antibodies as a novel and effective class of immunotherapeutics that combine the merits of traditional small molecule drug design with immunotherapy. ' 2006 Wiley-Liss, Inc.Key words: melanoma; angiogenesis; integrins; antibodies; tumor modelsThe discovery that tumor growth and metastasis are codependent on the formation of neovascularization 1 revealed many potential protein targets for cancer treatment. [2][3][4] The angiogenic process depends on proliferation of vascular endothelial cells, migration of tumor cells to the vascular endothelium followed by cell adhesion, and finally invasion of the endothelium. 5 A family of highly conserved adhesion molecules, known as integrins, is central to the regulation of these processes. Integrins are heterodimeric transmembrane receptor complexes composed of noncovalently associated a and b chains, and recognize the arginine-glycine-aspartic acid (RGD) sequence present in their extracellular matrix (ECM) ligands. 6 At present, 18 a and 8 b subunits are known; these form 24 different ab heterodimers with different specificity for various ECM cell-adhesive proteins. 7 Ligands for various integrins include fibronectin, collagen, laminin, von Willebrand factor, osteopontin, thrombospondin and vitronectin, all components of...

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“…In our results, we found four peptides but CASPSGALRSCpresenting phage, named PI, was the best candidate clone with the highest specificity for MDA-MB-231 cells and was thus selected for the following cellular binding assay (12). For comparison, RGD-integrin binding phage was introduced as a control, because it is known to be recognized and internalized by many types of human cells (28,29).…”

Section: Time -------------------------------------------------------mentioning

confidence: 91%

Characterization of PI (breast cancer cell special peptide) in MDA-MB-231 breast cancer cells and its potential therapeutic applications

Gao

Hong

Geng

et al. 2015

International Journal of Oncology

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Abstract. Gene therapy is one of the most important aspects of molecular targeted therapeutic approaches for tumors. A small molecule targeting carrier plays an important role in this process. PI, a new peptide found in our phage library, has been specifically suggested, combined with the human triple-negative breast cancer cell line MDA-MB-231, and may be developed as a targeting/individualization therapy strategy to be applied in breast cancer research. In this study, we further investigated whether this peptide could carry exogenous protein to the target cells by forming a fusion peptide. PI-GST and PI-TK were cloned into plasmids and used for expression studies, analyses of PI-mediated protein delivery efficiency, and to investigations into the effect of PI on thymidine kinase/ganciclovir-mediated cytotoxicity. Biodistribution profiles were also investigated in vivo. The results showed the PI fusion protein was expressed correctly in vitro, and could carry GST into the target cells. Under certain conditions, PI-TK sensitizes cells to ganciclovir more efficiently than TK. In vivo there was a trend for increased inhibition of tumor growth with PI-TK when ganciclovir was present. Therefore, our results suggest the potential of PI as a new specific target carrier in breast cancer therapy.

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Discovery of Orally Active Nonpeptide Vitronectin Receptor Antagonists Based on a 2-Benzazepine Gly-Asp Mimetic

Cited by 114 publications

References 28 publications

Breast adenocarcinoma cell adhesion to the vascular subendothelium in whole blood and under flow conditions: Effects of α v β 3 and α IIb β 3 antagonists

Breast adenocarcinoma cell adhesion to the vascular subendothelium in whole blood and under flow conditions: Effects of α v β 3 and α IIb β 3 antagonists

Small molecule drug activity in melanoma models may be dramatically enhanced with an antibody effector

Characterization of PI (breast cancer cell special peptide) in MDA-MB-231 breast cancer cells and its potential therapeutic applications

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