Discovery and structure-activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers.
As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.
Tai
Vincent W-F
VW
Celera Genomics, South San Francisco, CA 94080, USA. vince.tai@gmail.com
Sperandio
David
D
Shelton
Emma J
EJ
Litvak
Joane
J
Pararajasingham
Keith
K
Cebon
Ben
B
Lohman
Julia
J
Eksterowicz
John
J
Kantak
Seema
S
Sabbatini
Peter
P
Brown
Cindy
C
Zeitz
Jennifer
J
Reed
Chris
C
Maske
Bill
B
Graupe
Doris
D
Estevez
Alberto
A
Oeh
Jason
J
Wong
Darren
D
Ni
Yong
Y
Sprengeler
Paul
P
Yee
Robert
R
Magill
Catherine
C
Neri
Anthony
A
Cai
Sui Xiong
SX
Drewe
John
J
Qiu
Ling
L
Herich
John
J
Tseng
Ben
B
Kasibhatla
Shailaja
S
Spencer
Jeffrey R
JR
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000577:Amides; D010080:Oxazoles