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* Residue conservation analysis
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PDB id:
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Transferase, cell cycle
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Title:
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The structure of cdk2/cyclin a in complex with an oxindole inhibitor
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Structure:
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Cyclin-dependent kinase 2. Chain: a, c. Synonym: cdk2, p33 protein kinase. Engineered: yes. Cyclin a. Chain: b, d. Synonym: cyclin a2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
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Biol. unit:
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Dimer (from
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Resolution:
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2.80Å
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R-factor:
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0.260
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R-free:
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0.260
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Authors:
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S.T.Davis,B.G.Benson,H.N.Bramson,D.E.Chapman,S.H.Dickerson,K.M.Dold, D.J.Eberwein,M.Edelstein,S.V.Frye,R.T.Gampe Jr.,R.J.Griffin, P.A.Harris,A.M.Hassell,W.D.Holmes,R.N.Hunter,V.B.Knick,K.Lackey, B.Lovejoy,M.J.Luzzio,D.Murray,P.Parker,W.J.Rocque,L.Shewchuk, J.M.Veal,D.H.Walker,L.K.Kuyper
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Key ref:
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S.T.Davis
et al.
(2001).
Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.
Science,
291,
134-137.
PubMed id:
DOI:
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Date:
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20-Sep-00
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Release date:
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17-Jan-01
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PROCHECK
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Headers
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References
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Enzyme class 1:
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Chains A, C:
E.C.2.7.11.22
- cyclin-dependent kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Enzyme class 2:
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Chains B, D:
E.C.?
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Science
291:134-137
(2001)
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PubMed id:
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Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.
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S.T.Davis,
B.G.Benson,
H.N.Bramson,
D.E.Chapman,
S.H.Dickerson,
K.M.Dold,
D.J.Eberwein,
M.Edelstein,
S.V.Frye,
R.T.Gampe Jr,
R.J.Griffin,
P.A.Harris,
A.M.Hassell,
W.D.Holmes,
R.N.Hunter,
V.B.Knick,
K.Lackey,
B.Lovejoy,
M.J.Luzzio,
D.Murray,
P.Parker,
W.J.Rocque,
L.Shewchuk,
J.M.Veal,
D.H.Walker,
L.F.Kuyper.
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ABSTRACT
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Most traditional cytotoxic anticancer agents ablate the rapidly dividing
epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of
cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle
progression, may represent a therapeutic strategy for prevention of
chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the
sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent
small-molecule inhibitors of CDK2 were developed using structure-based methods.
Topical application of these compounds in a neonatal rat model of CIA reduced
hair loss at the site of application in 33 to 50% of the animals. Thus,
inhibition of CDK2 represents a potentially useful approach for the prevention
of CIA in cancer patients.
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Selected figure(s)
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Figure 1.
Fig. 1. (A) Chemical structures of compounds 1 to 4. (B) X-ray
crystallographic structure of CDK2 in complex with compound 3
(15). Atoms are color-coded as follows: protein carbon atoms,
green; nitrogen, blue; oxygen, red; sulfur, yellow; and bromine,
purple. The carbon atoms of compound 3 are shown in orange. The
indolinone (or oxindole) moiety of compound 3 was bound at the
back of the ATP site in a manner similar to that found for
members of the related series 2 in complex with fibroblast
growth factor (FGF) kinase (31). The oxindole amide group of 3
interacted with the strand of protein that connects the two
domains of CDK2, donating a hydrogen bond to the backbone
carbonyl of Glu81 and accepting a hydrogen bond from the
backbone NH of Leu83. The sulfonamidophenylhydrazone group
projected toward the opening of the cleft, with the sulfonamide
interacting with Asp86. The backbone NH of Asp86 donated a
hydrogen bond to one of the sulfonamide oxygen atoms, and the
side-chain carboxyl group accepted a hydrogen bond from the
sulfonamide amine function. (C) X-ray crystallographic structure
of compound 4 bound to CDK2-cyclin A. The carbon atoms of
compound 4 are shown in pink. The thiazole nitrogen atom at
position 5 of compound 4 accepted a hydrogen bond from Lys33,
and the thiazole sulfur atom at position 4 provided hydrophobic
interactions with Val18. The pyridyl substituent on the
sulfonamide group projected into solvent.
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Figure 4.
Fig. 4. Compound 4 prevents hair loss in a neonatal rat model
of CIA. Rat pups (13 days of age, actively growing hair) were
pretreated 4 hours and 2 hours (t =  4 and 2 hours)
with topical application of compound 4 (250 µg; 50
µl of 5 mg/ml DMSO) to the scalp, then injected with
etoposide. Etoposide induced total alopecia within 1 week of
administration. Hair was assessed and photographed on day 21.
The protective activity was schedule dependent. Two
applications, 4 hours and 2 hours before etoposide, were optimal
for protection. Post-treatment schedules were ineffective in
preventing hair loss. Shown are two animals from the untreated
group (- etoposide, upper left panel, animals 1 and 2); two
animals from DMSO-treated group (+ etoposide, upper right,
animals 3 and 4), and five animals from compound 4-treated group
(+ etoposide, lower panel, animals 5 to 9). Experiments were
repeated at least nine times with five rats per experimental
subgroup.
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The above figures are
reprinted
by permission from the AAAs:
Science
(2001,
291,
134-137)
copyright 2001.
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Figures were
selected
by an automated process.
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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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W.Ye,
and
S.W.Blain
(2011).
Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage.
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Apoptosis,
16,
449-459.
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H.Imanishi,
D.Tsuruta,
C.Tateishi,
K.Sugawara,
R.Paus,
T.Tsuji,
M.Ishii,
K.Ikeda,
H.Kunimoto,
K.Nakajima,
J.C.Jones,
and
H.Kobayashi
(2010).
Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia.
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J Dermatol Sci,
58,
43-54.
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N.Okimoto,
N.Futatsugi,
H.Fuji,
A.Suenaga,
G.Morimoto,
R.Yanai,
Y.Ohno,
T.Narumi,
and
M.Taiji
(2009).
High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations.
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PLoS Comput Biol,
5,
e1000528.
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H.M.Chen,
L.Wang,
and
S.R.D'Mello
(2008).
A chemical compound commonly used to inhibit PKR, {8-(imidazol-4-ylmethylene)-6H-azolidino[5,4-g] benzothiazol-7-one}, protects neurons by inhibiting cyclin-dependent kinase.
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Eur J Neurosci,
28,
2003-2016.
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H.González-Díaz,
L.Saíz-Urra,
R.Molina,
Y.González-Díaz,
and
A.Sánchez-González
(2007).
Computational chemistry approach to protein kinase recognition using 3D stochastic van der Waals spectral moments.
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J Comput Chem,
28,
1042-1048.
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K.Nakamura,
N.Yokoyama,
and
I.Igarashi
(2007).
Cyclin-dependent kinase inhibitors block erythrocyte invasion and intraerythrocytic development of Babesia bovis in vitro.
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Parasitology,
134,
1347-1353.
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G.A.Landrum,
J.E.Penzotti,
and
S.Putta
(2006).
Feature-map vectors: a new class of informative descriptors for computational drug discovery.
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J Comput Aided Mol Des,
20,
751-762.
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J.Sridhar,
N.Akula,
and
N.Pattabiraman
(2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
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AAPS J,
8,
E204-E221.
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A.Elis,
D.Blickstein,
Y.Manor,
and
M.Lishner
(2005).
Association between alopecia and response to chemotherapy in patients with Hodgkin lymphoma.
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Ther Drug Monit,
27,
287-289.
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H.Dureja,
and
A.K.Madan
(2005).
Topochemical models for prediction of cyclin-dependent kinase 2 inhibitory activity of indole-2-ones.
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J Mol Model,
11,
525-531.
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K.Johnson,
L.Liu,
N.Majdzadeh,
C.Chavez,
P.C.Chin,
B.Morrison,
L.Wang,
J.Park,
P.Chugh,
H.M.Chen,
and
S.R.D'Mello
(2005).
Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs.
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J Neurochem,
93,
538-548.
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B.B.Zhou,
and
J.Bartek
(2004).
Targeting the checkpoint kinases: chemosensitization versus chemoprotection.
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Nat Rev Cancer,
4,
216-225.
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D.Finlay,
S.Patel,
L.M.Dickson,
N.Shpiro,
R.Marquez,
C.J.Rhodes,
and
C.Sutherland
(2004).
Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element.
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BMC Mol Biol,
5,
15.
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D.J.Wolgemuth,
K.M.Lele,
V.Jobanputra,
and
G.Salazar
(2004).
The A-type cyclins and the meiotic cell cycle in mammalian male germ cells.
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Int J Androl,
27,
192-199.
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L.K.Pierson-Mullany,
and
C.A.Lange
(2004).
Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2.
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Mol Cell Biol,
24,
10542-10557.
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P.Cohen,
and
M.Goedert
(2004).
GSK3 inhibitors: development and therapeutic potential.
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Nat Rev Drug Discov,
3,
479-487.
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R.Paus,
and
K.Foitzik
(2004).
In search of the "hair cycle clock": a guided tour.
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Differentiation,
72,
489-511.
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N.C.Waters,
and
J.A.Geyer
(2003).
Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development.
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Expert Opin Ther Targets,
7,
7.
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V.A.Botchkarev
(2003).
Molecular mechanisms of chemotherapy-induced hair loss.
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J Investig Dermatol Symp Proc,
8,
72-75.
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E.A.Sausville
(2002).
Complexities in the development of cyclin-dependent kinase inhibitor drugs.
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Trends Mol Med,
8,
S32-S37.
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E.G.Nabel
(2002).
CDKs and CKIs: molecular targets for tissue remodelling.
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Nat Rev Drug Discov,
1,
587-598.
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I.R.Hardcastle,
B.T.Golding,
and
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(2002).
Designing inhibitors of cyclin-dependent kinases.
|
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Annu Rev Pharmacol Toxicol,
42,
325-348.
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M.Knockaert,
P.Greengard,
and
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(2002).
Pharmacological inhibitors of cyclin-dependent kinases.
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Trends Pharmacol Sci,
23,
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G.Redeuilh,
and
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(2002).
Cellular effects of purvalanol A: a specific inhibitor of cyclin-dependent kinase activities.
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Int J Cancer,
97,
761-769.
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(2002).
Progress toward the development of agents to modulate the cell cycle.
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and
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and
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Towards a molecular understanding of hair loss and its treatment.
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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.
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