title: Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856.
abstract: Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Stephane
authors.identifier: 0000-0001-8732-5243
authors.initials: S
authors.lastname: Perreault
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Chandrasekhar
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Cui
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Evarts
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Hao
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kaplan
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Kashishian
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Keegan
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kenney
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: David
authors.initials: D
authors.lastname: Koditek
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Latesh
authors.initials: L
authors.lastname: Lad
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Eve-Irene
authors.initials: EI
authors.lastname: Lepist
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: McGrath
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Bart
authors.initials: B
authors.lastname: Phillips
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Therrien
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Treiberg
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Anella
authors.initials: A
authors.lastname: Yahiaoui
authors.affiliation: Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human