Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists.
The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
Lucas
Brian S
BS
Department of Medicinal Chemistry, AMGEN, S. San Francisco, CA 94080, USA. blucas@amgen.com
Aaron
Wade
W
An
Songzhu
S
Austin
Richard J
RJ
Brown
Matthew
M
Chan
Hon
H
Chong
Angela
A
Hungate
Randall
R
Huang
Tom
T
Jiang
Ben
B
Johnson
Michael G
MG
Kaizerman
Jacob A
JA
Lee
Gary
G
McMinn
Dustin L
DL
Orf
Jessica
J
Powers
Jay P
JP
Rong
Minqing
M
Toteva
Maria M
MM
Uyeda
Craig
C
Wickramasinghe
Dineli
D
Xu
Guifen
G
Ye
Qiuping
Q
Zhong
Wendy
W
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D015195:Drug Design; D053823:Hedgehog Proteins; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000072086:Smoothened Receptor
D053823:Hedgehog Proteins; D010793:Phthalazines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D003577:Cytochrome P-450 Enzyme System