 |
PDBsum entry 3vs2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
3vs2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase/transferase inhibitor
|
|
|
Title:
|
|
Crystal structure of hck complexed with a pyrrolo-pyrimidine inhibitor 7-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7h- pyrrolo[2,3-d]pyrimidin-4-amine
|
|
Structure:
|
|
Tyrosine-protein kinase hck. Chain: a, b. Fragment: unp residues 81-526. Synonym: hematopoietic cell kinase, hemopoietic cell kinase, p59- hck/p60-hck, p59hck, p61hck. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: hck. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
|
|
Resolution:
|
|
|
2.61Å
|
R-factor:
|
0.228
|
R-free:
|
0.279
|
|
|
Authors:
|
|
M.Kuratani,Y.Tomabechi,H.Niwa,J.L.Parker,N.Handa,S.Yokoyama
|
|
Key ref:
|
|
Y.Saito
et al.
(2013).
A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo.
Sci Transl Med,
5,
181ra52.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
21-Apr-12
|
Release date:
|
01-May-13
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P08631
(HCK_HUMAN) -
Tyrosine-protein kinase HCK from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
526 a.a.
431 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
*
PDB and UniProt seqs differ
at 4 residue positions (black
crosses)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
|
|
|
|
|
|
|
Reaction:
|
|
L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
|
|
|
|
|
|
L-tyrosyl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-tyrosyl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Sci Transl Med
5:181ra52
(2013)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo.
|
|
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.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
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.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
