Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer.
The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.
Sutherlin
Daniel P
DP
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. sutherlin.dan@gene.com
Sampath
Deepak
D
Berry
Megan
M
Castanedo
Georgette
G
Chang
Zhigang
Z
Chuckowree
Irina
I
Dotson
Jenna
J
Folkes
Adrian
A
Friedman
Lori
L
Goldsmith
Richard
R
Heffron
Tim
T
Lee
Leslie
L
Lesnick
John
J
Lewis
Cristina
C
Mathieu
Simon
S
Nonomiya
Jim
J
Olivero
Alan
A
Pang
Jodie
J
Prior
Wei Wei
WW
Salphati
Laurent
L
Sideris
Steve
S
Tian
Qingping
Q
Tsui
Vickie
V
Wan
Nan Chi
NC
Wang
Shumei
S
Wiesmann
Christian
C
Wong
Susan
S
Zhu
Bing-Yan
BY
D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D058544:Class Ib Phosphatidylinositol 3-Kinase; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; C546843:mTOR protein, mouse; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases