title: A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.
abstract: Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.
authors.affiliation: Departments of Small Molecule Drug DiscoVery, Cell Cycle and Global Regulators, Translational Oncology, and Protein Engineering, Genentech, Inc, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Rawson
authors.forename: Matthias
authors.initials: M
authors.lastname: Rüth
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Dan
authors.initials: D
authors.lastname: Burdick
authors.forename: Laura
authors.initials: L
authors.lastname: Corson
authors.forename: Jenna
authors.initials: J
authors.lastname: Dotson
authors.forename: Jason
authors.initials: J
authors.lastname: Drummond
authors.forename: Carter
authors.initials: C
authors.lastname: Fields
authors.forename: Guy J
authors.initials: GJ
authors.lastname: Georges
authors.forename: Bernhard
authors.initials: B
authors.lastname: Goller
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunsaker
authors.forename: Tracy
authors.initials: T
authors.lastname: Kleinheinz
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Krell
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Anja
authors.initials: A
authors.lastname: Limberg
authors.forename: Angela
authors.initials: A
authors.lastname: McNutt
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.forename: Gail
authors.initials: G
authors.lastname: Phillips
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.forename: Brian
authors.initials: B
authors.lastname: Safina
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Leslie
authors.initials: L
authors.lastname: Walker
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
authors.forename: Petra
authors.initials: P
authors.lastname: Rüger
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
mesh_terms: D000284:Administration, Oral; D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D007769:Lactams / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
chemical_list: C531193:8-ethyl-2,5,6,12-tetrahydro-3,10,10-trimethyl-9-oxopyrazolo(4',3'-6,7)cyclohepta(1,2-b)pyrrolo(2,3-f)indole; D001562:Benzimidazoles; D006576:Heterocyclic Compounds, 4 or More Rings; D007769:Lactams; D047428:Protein Kinase Inhibitors; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576920:Aurka protein, rat; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases