title: Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity.
abstract: Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. chudin@gene.com
authors.forename: Chudi O
authors.initials: CO
authors.lastname: Ndubaku
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
authors.forename: Matthew
authors.initials: M
authors.lastname: Baumgardner
authors.forename: Nicole
authors.initials: N
authors.lastname: Blaquiere
authors.forename: Erin
authors.initials: E
authors.lastname: Bradley
authors.forename: Richard
authors.initials: R
authors.lastname: Bull
authors.forename: Steven
authors.initials: S
authors.lastname: Do
authors.forename: Jennafer
authors.initials: J
authors.lastname: Dotson
authors.forename: Danette
authors.initials: D
authors.lastname: Dudley
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Edgar
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Michelle
authors.initials: M
authors.lastname: Nannini
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Steve
authors.initials: S
authors.lastname: Price
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: Jeffery J
authors.initials: JJ
authors.lastname: Wallin
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D009368:Neoplasm Transplantation; D010077:Oxazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C582924:2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; D000970:Antineoplastic Agents; D007093:Imidazoles; D007527:Isoenzymes; D010077:Oxazepines; D000081082:Phosphoinositide-3 Kinase Inhibitors