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PDBsum entry 4a50
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PDB id:
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Cell cycle
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Title:
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Crystal structure of human kinesin eg5 in complex with 2-amino-5-(3- methylphenyl)-5,5-diphenylpentanoic acid
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Structure:
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Kinesin-like protein kif11. Chain: a. Fragment: motor domain, residues 1-368. Synonym: eg5, kinesin-like protein 1, kinesin-like spindle protein hk kinesin-related motor protein eg5, thyroid receptor-interacting protein 5, tr-interacting protein 5, trip-5. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plyss
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Resolution:
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2.75Å
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R-factor:
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0.200
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R-free:
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0.243
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Authors:
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H.Y.K.Kaan,F.Kozielski
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Key ref:
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F.Wang
et al.
(2012).
Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity.
J Med Chem,
55,
1511-1525.
PubMed id:
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Date:
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24-Oct-11
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Release date:
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31-Oct-12
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PROCHECK
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Headers
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References
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P52732
(KIF11_HUMAN) -
Kinesin-like protein KIF11 from Homo sapiens
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Seq:
Struc:
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1056 a.a.
336 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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J Med Chem
55:1511-1525
(2012)
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PubMed id:
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Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity.
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F.Wang,
J.A.Good,
O.Rath,
H.Y.Kaan,
O.B.Sutcliffe,
S.P.Mackay,
F.Kozielski.
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ABSTRACT
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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 K(i)(app) ≤ 10 nM and GI(50) ≈ 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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