title: The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326).
abstract: Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kβ relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.affiliation: Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Chudi
authors.initials: C
authors.lastname: Ndubaku
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.affiliation: Proteros Biostructures GmbH , Bunsenstr. 7aD, 82152 Martinsried, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Augistin
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Do
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Edgar
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.affiliation: Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Gancia
authors.affiliation: Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Jackson
authors.affiliation: Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Jones
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Kolesnikov
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Lesnick
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.affiliation: Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
authors.forename: Neville
authors.initials: N
authors.lastname: McLean
authors.affiliation: Proteros Biostructures GmbH , Bunsenstr. 7aD, 82152 Martinsried, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Mörtl
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Price
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
authors.affiliation: Proteros Biostructures GmbH , Bunsenstr. 7aD, 82152 Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steinbacher
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wallin
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001584:Benzoxepins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010077:Oxazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001584:Benzoxepins; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D007527:Isoenzymes; D010077:Oxazepines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C000609010:GDC-0326; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human