4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.
Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.
Liu
Kevin K-C
KK
Pfizer Global Research and Development, Chemistry Department, La Jolla, CA 92120, USA. kevin.k.liu@pfizer.com
Bagrodia
Shubha
S
Bailey
Simon
S
Cheng
Hengmiao
H
Chen
Hui
H
Gao
Lisa
L
Greasley
Samantha
S
Hoffman
Jacqui E
JE
Hu
Qiyue
Q
Johnson
Ted O
TO
Knighton
Dan
D
Liu
Zhengyu
Z
Marx
Matthew A
MA
Nambu
Mitchell D
MD
Ninkovic
Sacha
S
Pascual
Bernadette
B
Rafidi
Kristina
K
Rodgers
Caroline M-L
CM
Smith
Graham L
GL
Sun
Shaoxian
S
Wang
Haitao
H
Yang
Anle
A
Yuan
Jing
J
Zou
Aihua
A
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011621:Pteridines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D012995:Solubility; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D058570:TOR Serine-Threonine Kinases