2-Aminobenzimidazoles as potent Aurora kinase inhibitors.
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Zhong
Min
M
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA. mzhong@presidiopharma.com
Bui
Minna
M
Shen
Wang
W
Baskaran
Subramanian
S
Allen
Darin A
DA
Elling
Robert A
RA
Flanagan
W Michael
WM
Fung
Amy D
AD
Hanan
Emily J
EJ
Harris
Shannon O
SO
Heumann
Stacey A
SA
Hoch
Ute
U
Ivy
Sheryl N
SN
Jacobs
Jeffrey W
JW
Lam
Stuart
S
Lee
Heman
H
McDowell
Robert S
RS
Oslob
Johan D
JD
Purkey
Hans E
HE
Romanowski
Michael J
MJ
Silverman
Jeffrey A
JA
Tangonan
Bradley T
BT
Taverna
Pietro
P
Yang
Wenjin
W
Yoburn
Josh C
JC
Yu
Chul H
CH
Zimmerman
Kristin M
KM
O'Brien
Tom
T
Lew
Willard
W
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D064127:Aurora Kinases; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C027391:2-aminobenzimidazole; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases