Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.
Adams
Nicholas D
ND
Cancer Research, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. nicholas.d.adams@gsk.com
Adams
Jerry L
JL
Burgess
Joelle L
JL
Chaudhari
Amita M
AM
Copeland
Robert A
RA
Donatelli
Carla A
CA
Drewry
David H
DH
Fisher
Kelly E
KE
Hamajima
Toshihiro
T
Hardwicke
Mary Ann
MA
Huffman
William F
WF
Koretke-Brown
Kristin K
KK
Lai
Zhihong V
ZV
McDonald
Octerloney B
OB
Nakamura
Hiroko
H
Newlander
Ken A
KA
Oleykowski
Catherine A
CA
Parrish
Cynthia A
CA
Patrick
Denis R
DR
Plant
Ramona
R
Sarpong
Martha A
MA
Sasaki
Kosuke
K
Schmidt
Stanley J
SJ
Silva
Domingos J
DJ
Sutton
David
D
Tang
Jun
J
Thompson
Christine S
CS
Tummino
Peter J
PJ
Wang
Jamin C
JC
Xiang
Hong
H
Yang
Jingsong
J
Dhanak
Dashyant
D
D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D001372:Aza Compounds; C544308:GSK 1070916; D006657:Histones; D007211:Indoles; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases