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PDBsum entry 3vs2
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Transferase/transferase inhibitor
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PDB id
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3vs2
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References listed in PDB file
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Key reference
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Title
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A pyrrolo-Pyrimidine derivative targets human primary aml stem cells in vivo.
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Authors
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Y.Saito,
H.Yuki,
M.Kuratani,
Y.Hashizume,
S.Takagi,
T.Honma,
A.Tanaka,
M.Shirouzu,
J.Mikuni,
N.Handa,
I.Ogahara,
A.Sone,
Y.Najima,
Y.Tomabechi,
M.Wakiyama,
N.Uchida,
M.Tomizawa-Murasawa,
A.Kaneko,
S.Tanaka,
N.Suzuki,
H.Kajita,
Y.Aoki,
O.Ohara,
L.D.Shultz,
T.Fukami,
T.Goto,
S.Taniguchi,
S.Yokoyama,
F.Ishikawa.
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Ref.
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Sci Transl Med, 2013,
5,
181ra52.
[DOI no: ]
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PubMed id
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Abstract
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Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to
contribute to disease relapse, leading to poor long-term outcomes for patients
with acute myeloid leukemia (AML). We previously identified a Src-family kinase
(SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is
highly differentially expressed in human primary LSCs compared with human normal
hematopoietic stem cells (HSCs). We performed a large-scale chemical library
screen that integrated a high-throughput enzyme inhibition assay, in silico
binding prediction, and crystal structure determination and found a candidate
HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50
(half maximal inhibitory concentration) in the subnanomolar range. A crystal
structure revealed that RK-20449 bound the activation pocket of HCK. In vivo
administration of RK-20449 to nonobese diabetic (NOD)/severe combined
immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive
therapy-resistant AML significantly reduced human LSC and non-stem AML burden.
By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse
and lead to improved patient outcomes in AML.
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