 |
PDBsum entry 6tns
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Optimization of orally bioavailable pi3kδ inhibitors and identification of vps34 as a key selectivity target.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
J Med Chem, 2020,
63,
638-655.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
