 |
PDBsum entry 7lm2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
7lm2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Projected dose optimization of amino- And hydroxypyrrolidine purine pi3kδ immunomodulators.
|
|
|
Authors
|
|
J.L.Methot,
H.Zhou,
M.A.Mcgowan,
N.J.Anthony,
M.Christopher,
Y.Garcia,
A.Achab,
K.Lipford,
B.W.Trotter,
M.D.Altman,
X.Fradera,
C.A.Lesburg,
C.Li,
S.Alves,
C.P.Chappell,
R.Jain,
R.Mangado,
E.Pinheiro,
S.M.G.Williams,
P.Goldenblatt,
A.Hill,
L.Shaffer,
D.Chen,
V.Tong,
R.L.Mcleod,
H.H.Lee,
H.Yu,
S.Shah,
J.D.Katz.
|
|
|
Ref.
|
|
J Med Chem, 2021,
64,
5137-5156.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for
the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our
program led to the identification of structurally distinct heterocycloalkyl
purine inhibitors with excellent isoform and kinome selectivity; however, they
had high projected human doses. Improved ligand contacts gave potency
enhancements, while replacement of metabolic liabilities led to extended
half-lives in preclinical species, affording PI3Kδ inhibitors with low
once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice
with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in
Foxp3-expressing regulatory T cells as observed through bioluminescence imaging
with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell
proliferation. As a model for allergic rhinitis and asthma, treatment of
ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c
gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation
eosinophil cell count.
|
|
|
|
|
|
|
