Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity

F. Wang, J. A. D. Good, O. Rath, H. Y. K. Kaan, O. B. Sutcliffe, S. P. Mackay, F. Kozielski

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages1511-1525
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number4
Early online date16 Jan 2012
DOIs
Publication statusPublished - 23 Feb 2012

Fingerprint

Kinesin
Cysteine
Allosteric Site
Benchmarking
Spindle Apparatus
Proteins
Heterografts
Nude Mice
Biological Availability
Amines
Drug Therapy
Growth
ispinesib
Neoplasms

Keywords

  • trityl-l-cysteine
  • amino-acids
  • human ksp
  • marfeys method
  • mechanism
  • motor
  • EG5
  • cancer
  • absolute-configuration
  • ISPINESIB

Cite this

Wang, F., Good, J. A. D., Rath, O., Kaan, H. Y. K., Sutcliffe, O. B., Mackay, S. P., & Kozielski, F. (2012). Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity. Journal of Medicinal Chemistry, 55(4), 1511-1525. https://doi.org/10.1021/jm201195m
Wang, F. ; Good, J. A. D. ; Rath, O. ; Kaan, H. Y. K. ; Sutcliffe, O. B. ; Mackay, S. P. ; Kozielski, F. / Triphenylbutanamines : kinesin spindle protein inhibitors with in vivo antitumor activity. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 4. pp. 1511-1525.
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abstract = "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.",
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Wang, F, Good, JAD, Rath, O, Kaan, HYK, Sutcliffe, OB, Mackay, SP & Kozielski, F 2012, 'Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity' Journal of Medicinal Chemistry, vol. 55, no. 4, pp. 1511-1525. https://doi.org/10.1021/jm201195m

Triphenylbutanamines : kinesin spindle protein inhibitors with in vivo antitumor activity. / Wang, F.; Good, J. A. D.; Rath, O.; Kaan, H. Y. K.; Sutcliffe, O. B.; Mackay, S. P.; Kozielski, F.

In: Journal of Medicinal Chemistry, Vol. 55, No. 4, 23.02.2012, p. 1511-1525.

Research output: Contribution to journalArticle

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AU - Kaan, H. Y. K.

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AU - Mackay, S. P.

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