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PDBsum entry 4tth
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Transferase/cell cycle/inhibitor
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PDB id
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4tth
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References listed in PDB file
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Key reference
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Title
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Discovery of amg 925, A flt3 and cdk4 dual kinase inhibitor with preferential affinity for the activated state of flt3.
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Authors
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Z.Li,
X.Wang,
J.Eksterowicz,
M.W.Gribble,
G.Q.Alba,
M.Ayres,
T.J.Carlson,
A.Chen,
X.Chen,
R.Cho,
R.V.Connors,
M.Degraffenreid,
J.T.Deignan,
J.Duquette,
P.Fan,
B.Fisher,
J.Fu,
J.N.Huard,
J.Kaizerman,
K.S.Keegan,
C.Li,
K.Li,
Y.Li,
L.Liang,
W.Liu,
S.E.Lively,
M.C.Lo,
J.Ma,
D.L.Mcminn,
J.T.Mihalic,
K.Modi,
R.Ngo,
K.Pattabiraman,
D.E.Piper,
C.Queva,
M.L.Ragains,
J.Suchomel,
S.Thibault,
N.Walker,
X.Wang,
Z.Wang,
M.Wanska,
P.M.Wehn,
M.F.Weidner,
A.J.Zhang,
X.Zhao,
A.Kamb,
D.Wickramasinghe,
K.Dai,
L.R.Mcgee,
J.C.Medina.
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Ref.
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J Med Chem, 2014,
57,
3430-3449.
[DOI no: ]
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PubMed id
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Abstract
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We describe the structural optimization of a lead compound 1 that exhibits dual
inhibitory activities against FLT3 and CDK4. A series of
pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR
analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a
potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many
FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel
of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and
induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)),
which exhibits resistance to a number of FLT3 inhibitors currently under
clinical development. At well-tolerated doses, compound 28 leads to significant
growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates
with inhibition of STAT5 and Rb phosphorylation.
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