title: 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.
abstract: 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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. sutherlin.dan@gene.com
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Megan
authors.initials: M
authors.lastname: Berry
authors.forename: Georgette
authors.initials: G
authors.lastname: Castanedo
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Chang
authors.forename: Irina
authors.initials: I
authors.lastname: Chuckowree
authors.forename: Jenna
authors.initials: J
authors.lastname: Dotson
authors.forename: Adrian
authors.initials: A
authors.lastname: Folkes
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Tim
authors.initials: T
authors.lastname: Heffron
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Alan
authors.initials: A
authors.lastname: Olivero
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Qingping
authors.initials: Q
authors.lastname: Tian
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Nan Chi
authors.initials: NC
authors.lastname: Wan
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: 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
chemical_list: 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