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Open Access research which pushes advances in bionanotechnology

Strathprints makes available scholarly Open Access content by researchers in the Strathclyde Institute of Pharmacy & Biomedical Sciences (SIPBS) , based within the Faculty of Science.

SIPBS is a major research centre in Scotland focusing on 'new medicines', 'better medicines' and 'better use of medicines'. This includes the exploration of nanoparticles and nanomedicines within the wider research agenda of bionanotechnology, in which the tools of nanotechnology are applied to solve biological problems. At SIPBS multidisciplinary approaches are also pursued to improve bioscience understanding of novel therapeutic targets with the aim of developing therapeutic interventions and the investigation, development and manufacture of drug substances and products.

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Optimized s-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models

Good, James A. D. and Wang, Fang and Rath, Oliver and Kaan, Hung Yi Kristal and Talapatra, Sandeep K. and Podgorski, Dawid and MacKay, Simon P. and Kozielski, Frank (2013) Optimized s-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models. Journal of Medicinal Chemistry, 56 (5). pp. 1878-1893. ISSN 0022-2623

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Abstract

The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K-i(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacolcinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.