Wang, F. and Good, J. A. D. and Rath, O. and Kaan, H. Y. K. and Sutcliffe, O. B. and Mackay, S. P. and Kozielski, F. (2012) Triphenylbutanamines : kinesin spindle protein inhibitors with in vivo antitumor activity. Journal of Medicinal Chemistry, 55 (4). pp. 1511-1525. ISSN 0022-2623Full text not available in this repository. (Request a copy from the Strathclyde author)
The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit Kiapp ≤ 10 nM and GI50 ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.
|Keywords:||trityl-l-cysteine, amino-acids, human ksp, marfeys method, mechanism, motor, EG5, cancer, absolute-configuration, ISPINESIB, Pharmacy and materia medica, Drug Discovery, Molecular Medicine|
|Subjects:||Medicine > Pharmacy and materia medica|
|Department:||Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences|
|Depositing user:||Pure Administrator|
|Date Deposited:||29 Jun 2012 14:41|
|Last modified:||27 Apr 2016 18:46|