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PDBsum entry 4poj
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Transcription
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PDB id
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4poj
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References listed in PDB file
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Key reference
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Title
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Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
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Authors
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V.R.Atigadda,
G.Xia,
A.Desphande,
L.J.Boerma,
S.Lobo-Ruppert,
C.J.Grubbs,
C.D.Smith,
W.J.Brouillette,
D.D.Muccio.
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Ref.
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J Med Chem, 2014,
57,
5370-5380.
[DOI no: ]
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PubMed id
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Abstract
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(2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic
acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive
capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a
potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To
evaluate how methyl substitution influenced potency and lipid biosynthesis, we
synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-,
or 8-position of the tetralone ring. The syntheses and biological evaluations of
these new analogues are reported here along with the X-ray crystal structures of
each homologue bound to the ligand binding domain of hRXRα. We demonstrate that
each homologue of 9cUAB30 is a more potent agonist, but only the
7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray
crystal structures of these new rexinoids and bexarotene (Targretin) bound to
hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had
methyl groups that interacted with helix 7 residues of the LBD.
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