Design and synthesis of alpha-ketoamides as cathepsin S inhibitors with potential applications against tumor invasion and angiogenesis.
A series of small molecules bearing an alpha-ketoamide warhead were synthesized and evaluated for their ability to inhibit cathepsin S, a key proteolytic enzyme upregulated in many cancers during tumor progression and metastasis. Most of the synthetic compounds were noncytotoxic, but several robustly inhibited cathepsin S (IC(50) < 10 nM) and potently suppressed cell migration, invasion, and capillary tube formation. These results highlight the potential of alpha-ketoamide therapy for preventing or delaying cancer spread.
Chen
Jo-Chun
JC
Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
Uang
Biing-Jiun
BJ
Lyu
Ping-Chiang
PC
Chang
Jang-Yang
JY
Liu
Ko-Jiunn
KJ
Kuo
Ching-Chuan
CC
Hsieh
Hsing-Pang
HP
Wang
Hsin-Chieh
HC
Cheng
Chao-Sheng
CS
Chang
Yi-Hsun
YH
Chang
Margaret Dah-Tsyr
MD
Chang
Wun-Shaing Wayne
WS
Lin
Chun-Cheng
CC
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation
D000577:Amides; D011480:Protease Inhibitors; D002403:Cathepsins; C028217:cathepsin S