GDC-0449-a potent inhibitor of the hedgehog pathway.
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Robarge
Kirk D
KD
Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA 94080, United States. kir@gene.com
Brunton
Shirley A
SA
Castanedo
Georgette M
GM
Cui
Yong
Y
Dina
Michael S
MS
Goldsmith
Richard
R
Gould
Stephen E
SE
Guichert
Oivin
O
Gunzner
Janet L
JL
Halladay
Jason
J
Jia
Wei
W
Khojasteh
Cyrus
C
Koehler
Michael F T
MF
Kotkow
Karen
K
La
Hank
H
Lalonde
Rebecca L
RL
Lau
Kevin
K
Lee
Leslie
L
Marshall
Derek
D
Marsters
James C
JC
Murray
Lesley J
LJ
Qian
Changgeng
C
Rubin
Lee L
LL
Salphati
Laurent
L
Stanley
Mark S
MS
Stibbard
John H A
JH
Sutherlin
Daniel P
DP
Ubhayaker
Savita
S
Wang
Shumei
S
Wong
Susan
S
Xie
Minli
M
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D002280:Basal Cell Carcinoma / Q000188:drug therapy; D002460:Cell Line; D002528:Cerebellar Neoplasms / Q000188:drug therapy; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000577:Amides; D000813:Anilides; D001562:Benzimidazoles; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines