A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.
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.
Rawson
Thomas E
TE
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.
Rüth
Matthias
M
Blackwood
Elizabeth
E
Burdick
Dan
D
Corson
Laura
L
Dotson
Jenna
J
Drummond
Jason
J
Fields
Carter
C
Georges
Guy J
GJ
Goller
Bernhard
B
Halladay
Jason
J
Hunsaker
Thomas
T
Kleinheinz
Tracy
T
Krell
Hans-Willi
HW
Li
Jun
J
Liang
Jun
J
Limberg
Anja
A
McNutt
Angela
A
Moffat
John
J
Phillips
Gail
G
Ran
Yingqing
Y
Safina
Brian
B
Ultsch
Mark
M
Walker
Leslie
L
Wiesmann
Christian
C
Zhang
Birong
B
Zhou
Aihe
A
Zhu
Bing-Yan
BY
Rüger
Petra
P
Cochran
Andrea G
AG
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
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