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PDBsum entry 3cjo
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Motor protein
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PDB id
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3cjo
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Contents |
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* Residue conservation analysis
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PDB id:
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Motor protein
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Title:
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Crystal structure of ksp in complex with inhibitor 30
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Structure:
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Kinesin-like protein kif11. Chain: a, b. Synonym: kinesin-related motor protein eg5, kinesin-like spindle protein hksp, thyroid receptor-interacting protein 5, trip-5, kinesin-like protein 1. Engineered: yes
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Source:
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Homo sapiens. Human. Gene: kif11, eg5, knsl1, trip5. Expressed in: escherichia coli.
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Resolution:
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2.28Å
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R-factor:
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0.185
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R-free:
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0.261
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Authors:
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Y.Yan
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Key ref:
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C.D.Cox
et al.
(2008).
Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer.
J Med Chem,
51,
4239-4252.
PubMed id:
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Date:
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13-Mar-08
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Release date:
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01-Jul-08
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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.
330 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
51:4239-4252
(2008)
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PubMed id:
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Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer.
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C.D.Cox,
P.J.Coleman,
M.J.Breslin,
D.B.Whitman,
R.M.Garbaccio,
M.E.Fraley,
C.A.Buser,
E.S.Walsh,
K.Hamilton,
M.D.Schaber,
R.B.Lobell,
W.Tao,
J.P.Davide,
R.E.Diehl,
M.T.Abrams,
V.J.South,
H.E.Huber,
M.Torrent,
T.Prueksaritanont,
C.Li,
D.E.Slaughter,
E.Mahan,
C.Fernandez-Metzler,
Y.Yan,
L.C.Kuo,
N.E.Kohl,
G.D.Hartman.
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ABSTRACT
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Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment
of cancer with the potential to overcome limitations associated with currently
employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole
KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo
potency, issues that limited earlier compounds from our program. However,
introduction of the C2-hydroxymethyl group caused 11 to be a substrate for
cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from
previous KSP inhibitors, we found that beta-fluorination modulated the p K a of
the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14)
generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic,
metabolically benign position by synthesis of an
N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an
optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently
studied in a phase I clinical trial in patients with taxane-refractory solid
tumors.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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O.Rath,
and
F.Kozielski
(2012).
Kinesins and cancer.
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Nat Rev Cancer,
12,
527-539.
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S.K.Talapatra,
A.W.Schüttelkopf,
and
F.Kozielski
(2012).
The structure of the ternary Eg5-ADP-ispinesib complex.
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Acta Crystallogr D Biol Crystallogr,
68,
1311-1319.
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PDB code:
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C.Jiang,
Q.You,
F.Liu,
W.Wu,
Q.Guo,
J.Chern,
L.Yang,
and
M.Chen
(2009).
Design, synthesis and evaluation of tetrahydroisoquinolines as new kinesin spindle protein inhibitors.
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Chem Pharm Bull (Tokyo),
57,
567-571.
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D.Huszar,
M.E.Theoclitou,
J.Skolnik,
and
R.Herbst
(2009).
Kinesin motor proteins as targets for cancer therapy.
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Cancer Metastasis Rev,
28,
197-208.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
