Doing the Methylene Shuffle – Further Insights into the Inhibition of Mitotic Kinesin Eg5 with S-Trityl L-Cysteine

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Journal Title, Volume, Page: 
European Journal of Medicinal Chemistry Volume 54, August 2012, Pages 483–498
Year of Publication: 
2012
Authors: 
Murad N. Abualhasan
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
James A.D. Good
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
Kitiyaporn Wittayanarakul
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Nahoum G. Anthony
Giacomo Berretta
Oliver Rath
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
Frank Kozielski
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
Oliver B. Sutcliffe
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Simon P. Mackay
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Preferred Abstract (Original): 

S-Trityl l-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand–protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines.

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