Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.
A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. sutherd1@gene.com
Daniel P
DP
Sutherlin
Stewart
S
Baker
Angelina
A
Bisconte
Paul M
PM
Blaney
Anthony
A
Brown
Bryan K
BK
Chan
David
D
Chantry
Georgette
G
Castanedo
Paul
P
DePledge
Paul
P
Goldsmith
David M
DM
Goldstein
Timothy
T
Hancox
Jasmit
J
Kaur
David
D
Knowles
Rama
R
Kondru
John
J
Lesnick
Matthew C
MC
Lucas
Cristina
C
Lewis
Jeremy
J
Murray
Alan J
AJ
Nadin
Jim
J
Nonomiya
Jodie
J
Pang
Neil
N
Pegg
Steve
S
Price
Karin
K
Reif
Brian S
BS
Safina
Laurent
L
Salphati
Steven
S
Staben
Eileen M
EM
Seward
Stephen
S
Shuttleworth
Sukhjit
S
Sohal
Zachary K
ZK
Sweeney
Mark
M
Ultsch
Bohdan
B
Waszkowycz
Binqing
B
Wei
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D005260:Female; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry*
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D014364:Tryptophan