OptimizedS-trityl-l-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models

Good, J.A.D., Wang, F., Rath, O., Kaan, H.Y.K., Talapatra, S.K., Podgórski, D., MacKay, S.P. and Kozielski, F. (2013) OptimizedS-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. (doi: 10.1021/jm3014597)

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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 (Kiapp < 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 pharmacokinetics 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kozielski, Professor Frank and Talapatra, Mr Sandeep and Good, Mr James and Rath, Dr Oliver
Authors: Good, J.A.D., Wang, F., Rath, O., Kaan, H.Y.K., Talapatra, S.K., Podgórski, D., MacKay, S.P., and Kozielski, F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Medicinal Chemistry
ISSN:0022-2623
ISSN (Online):1520-4804
Published Online:01 February 2013

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