1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.
Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.
Miller-Moslin
Karen
K
Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 01239, USA. karen.miller@novartis.com
Peukert
Stefan
S
Jain
Rishi K
RK
McEwan
Michael A
MA
Karki
Rajesh
R
Llamas
Luis
L
Yusuff
Naeem
N
He
Feng
F
Li
Yanhong
Y
Sun
Yingchuan
Y
Dai
Miao
M
Perez
Lawrence
L
Michael
Walter
W
Sheng
Tao
T
Lei
Huangshu
H
Zhang
Rui
R
Williams
Juliet
J
Bourret
Aaron
A
Ramamurthy
Arun
A
Yuan
Jing
J
Guo
Ribo
R
Matsumoto
Melissa
M
Vattay
Anthony
A
Maniara
Wieslawa
W
Amaral
Adam
A
Dorsch
Marion
M
Kelleher
Joseph F
JF
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010793:Phthalazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D010793:Phthalazines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor