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PDBsum entry 4bzo
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PDB id:
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Transferase
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Title:
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Crystal structure of pim1 in complex with a pyrrolo-pyrazinone inhibitor
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Structure:
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Serine/threonine-protein kinase pim-1. Chain: a. Fragment: kinase domain, residues 2-313. Synonym: proto-oncogene serine threonine-protein kinase pim-1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.10Å
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R-factor:
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0.183
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R-free:
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0.216
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Authors:
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E.Casale,F.Casuscelli,E.Ardini,N.Avanzi,G.Cervi,M.D'Anello,D.Donati, D.Faiardi,R.D.Ferguson,G.Fogliatto,A.Galvani,A.Marsiglio, D.G.Mirizzi,M.Montemartini,C.Orrenius,G.Papeo,C.Piutti,B.Salom, E.R.Felder
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Key ref:
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F.Casuscelli
et al.
(2013).
Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.
Bioorg Med Chem Lett,
21,
7364-7380.
PubMed id:
DOI:
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Date:
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29-Jul-13
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Release date:
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30-Oct-13
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PROCHECK
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Headers
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References
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P11309
(PIM1_HUMAN) -
Serine/threonine-protein kinase pim-1 from Homo sapiens
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Seq:
Struc:
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313 a.a.
273 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
21:7364-7380
(2013)
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PubMed id:
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Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.
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F.Casuscelli,
E.Ardini,
N.Avanzi,
E.Casale,
G.Cervi,
M.D'Anello,
D.Donati,
D.Faiardi,
R.D.Ferguson,
G.Fogliatto,
A.Galvani,
A.Marsiglio,
D.G.Mirizzi,
M.Montemartini,
C.Orrenius,
G.Papeo,
C.Piutti,
B.Salom,
E.R.Felder.
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ABSTRACT
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A novel series of PIM inhibitors was derived from a combined effort in natural
product-inspired library generation and screening. The novel
pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50
values in the low micromolar range. The application of a rational optimization
strategy, guided by the determination of the crystal structure of the complex in
the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a,
which is a potent PIM kinases inhibitor exhibiting excellent selectivity against
a large panel of kinases, representative of each family. The synthesis,
structure-activity relationship studies, and pharmacokinetic data of compounds
from this inhibitor class are presented herein. Furthermore, the cellular
activities including inhibition of cell growth and modulation of downstream
targets are also described.
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Links
