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PDBsum entry 3et3
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Transcription
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PDB id
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3et3
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References listed in PDB file
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Key reference
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Title
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Scaffold-Based discovery of indeglitazar, A ppar pan-Active anti-Diabetic agent.
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Authors
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D.R.Artis,
J.J.Lin,
C.Zhang,
W.Wang,
U.Mehra,
M.Perreault,
D.Erbe,
H.I.Krupka,
B.P.England,
J.Arnold,
A.N.Plotnikov,
A.Marimuthu,
H.Nguyen,
S.Will,
M.Signaevsky,
J.Kral,
J.Cantwell,
C.Settachatgull,
D.S.Yan,
D.Fong,
A.Oh,
S.Shi,
P.Womack,
B.Powell,
G.Habets,
B.L.West,
K.Y.Zhang,
M.V.Milburn,
G.P.Vlasuk,
K.P.Hirth,
K.Nolop,
G.Bollag,
P.N.Ibrahim,
J.F.Tobin.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
262-267.
[DOI no: ]
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PubMed id
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Abstract
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In a search for more effective anti-diabetic treatment, we used a process
coupling low-affinity biochemical screening with high-throughput
co-crystallography in the design of a series of compounds that selectively
modulate the activities of all three peroxisome proliferator-activated receptors
(PPARs), PPARalpha, PPARgamma, and PPARdelta. Transcriptional transactivation
assays were used to select compounds from this chemical series with a bias
toward partial agonism toward PPARgamma, to circumvent the clinically observed
side effects of full PPARgamma agonists. Co-crystallographic characterization of
the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed
the structural basis for its PPAR pan-activity and its partial agonistic
response toward PPARgamma. Compared with full PPARgamma-agonists, indeglitazar
is less potent in promoting adipocyte differentiation and only partially
effective in stimulating adiponectin gene expression. Evaluation of the compound
in vivo confirmed the reduced adiponectin response in animal models of obesity
and diabetes while revealing strong beneficial effects on glucose,
triglycerides, cholesterol, body weight, and other metabolic parameters.
Indeglitazar has now progressed to Phase II clinical evaluations for Type 2
diabetes mellitus (T2DM).
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Figure 1.
Discovery and structural characterization of indeglitazar.
(A) Crystal structure of scaffold 1 with PPARγ. The blue mesh
encompassing 1 delineates the productive hydrophobic interaction
space common to PPARα, PPARγ, and PPARδ (see SI Experimental
Procedures). The 4 residues shown in sticks comprise the core
signaling linkage to the ligand acidic moiety. (B) Overlap of
indeglitazar in complex with PPARα (red), PPARγ (green), and
PPARδ (blue). (C–E) Close-up of the individual structures in
the region highlighted from B. Note the water-mediated
interactions in D and E. The chemical structures of the
compounds 1, 2, and 3 (indeglitazar) are shown.
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Figure 2.
Cellular activity of indeglitazar and its effect on the
expression of adiponectin and in vivo adiponectin response.
(A–C) Transactivation assay activity of indeglitazar (filled
circles) and reference compound (open circles) in PPARα,
PPARγ, and PPARδ, respectively. Note the partial response of
indeglitazar toward PPARγ. (D) Preadipocyte differentiation
stimulated by rosiglitazone (open circles) and indeglitazar
(filled circles). (E) Taqman analysis of the expression of
adiponectin by mature adipocytes treated by indeglitazar and
rosiglitazone. (F) Effect of indeglitazar and pioglitazone on
adiponectin levels in the ob/ob mice after 14 days of treatment.
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