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PDBsum entry 1fvv
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Transferase, cell cycle
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PDB id
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1fvv
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Prevention of chemotherapy-Induced alopecia in rats by cdk inhibitors.
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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.F.Kuyper.
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Ref.
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Science, 2001,
291,
134-137.
[DOI no: ]
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PubMed id
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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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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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