 |
PDBsum entry 6tns
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase
|
|
|
Title:
|
|
Pi3k delta in complex with 2methoxyn[2methoxy5(7{[(2r)4(oxetan3 yl) morpholin2yl]methoxy}1,3dihydro2 benzofuran5yl)pyridin3yl]ethane1 sulfonamide
|
|
Structure:
|
|
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform. Chain: a. Synonym: ptdins-3-kinase subunit delta,phosphatidylinositol 4,5- bisphosphate 3-kinase 110 kda catalytic subunit delta,p110delta. Engineered: yes
|
|
Source:
|
|
Mus musculus. House mouse. Organism_taxid: 10090. Gene: pik3cd. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
|
|
Resolution:
|
|
|
2.40Å
|
R-factor:
|
0.190
|
R-free:
|
0.244
|
|
|
Authors:
|
|
M.A.Convery,P.Rowland,Z.A.Henley,N.Barton,K.Down
|
|
Key ref:
|
|
Z.A.Henley
et al.
(2020).
Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target.
J Med Chem,
63,
638-655.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
10-Dec-19
|
Release date:
|
01-Jan-20
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
O35904
(PK3CD_MOUSE) -
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform from Mus musculus
|
|
|
|
Seq:
Struc:
|
|
|
|
1043 a.a.
863 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
|
*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class 2:
|
|
E.C.2.7.1.137
- phosphatidylinositol 3-kinase.
|
|
|
|
|
|
|
Pathway:
|
|
1-Phosphatidyl-myo-inositol Metabolism
|
|
|
|
|
|
Reaction:
|
|
a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H+
|
|
|
|
|
|
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol)
|
+
|
ATP
|
=
|
1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate)
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
Enzyme class 3:
|
|
E.C.2.7.1.153
- phosphatidylinositol-4,5-bisphosphate 3-kinase.
|
|
|
|
|
|
|
Pathway:
|
|
|
|
|
|
|
|
Reaction:
|
|
a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H+
|
|
|
|
|
|
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate)
|
+
|
ATP
|
=
|
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate)
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
63:638-655
(2020)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target.
|
|
Z.A.Henley,
A.Amour,
N.Barton,
M.Bantscheff,
G.Bergamini,
S.M.Bertrand,
M.Convery,
K.Down,
B.Dümpelfeld,
C.D.Edwards,
P.Grandi,
P.M.Gore,
S.Keeling,
S.Livia,
D.Mallett,
A.Maxwell,
M.Price,
C.Rau,
F.B.M.Reinhard,
J.Rowedder,
P.Rowland,
J.A.Taylor,
D.A.Thomas,
E.M.Hessel,
J.N.Hamblin.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Optimization of a lead series of PI3Kδ inhibitors based on a
dihydroisobenzofuran core led to the identification of potent, orally
bioavailable compound 19. Selectivity profiling of compound 19
showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound
19 was not well-tolerated in a 7-day rat toxicity study. Structure-based
design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus
on oral phramacokinetics properties resulted in the discovery of compound
41, which showed improved toxicological outcomes at similar exposure
levels to compound 19.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
