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Ness K.A.,Queens University of Belfast | Eddie S.L.,Queens University of Belfast | Burton S.,Almac Discovery | Harrison T.,Almac Discovery | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

This letter describes the design, development and SAR exploration of a novel series of small legumain inhibitors. The SAR of a new small molecule legumain inhibitor chemotype was explored and found to have improved physiochemical properties compared to previously developed inhibitors within our group. However, further development of this series was found to be limited as the SAR was observed to be relatively flat. © 2015 Elsevier B.V. All rights reserved. Source


Higgins C.,Queens University of Belfast | Bouazzaoui S.,Queens University of Belfast | Gaddale K.,Queens University of Belfast | D'Costa Z.,Queens University of Belfast | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

This Letter describes the further development and SAR exploration of a novel series of Legumain inhibitors. Based upon a previously identified Legumain inhibitor from our group, we explored the SAR of the carbamate phenyl ring system to probe the P3 pocket of the enzyme. This led to the identification of a sub-nanomolar inhibitor of Legumain. © 2014 Elsevier Ltd. All rights reserved. Source


Valentine A.,Queens University of Belfast | O'Rourke M.,Queens University of Belfast | Yakkundi A.,Queens University of Belfast | Worthington J.,University of Ulster | And 15 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action. Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status. Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL's antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype. Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy. ©2011 AACR. Source


Ness K.A.,Queens University of Belfast | Eddie S.L.,Queens University of Belfast | Higgins C.A.,Queens University of Belfast | Templeman A.,Queens University of Belfast | And 12 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays. © 2015 Elsevier Ltd. All rights reserved. Source

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