Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors.
A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model.
Chen
Chih-Hung
CH
Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan. ChihHungChen@itri.org.tw
Lee
On
O
Yao
Chung-Niang
CN
Chuang
Meng-Yun
MY
Chang
Yow-Lone
YL
Chang
May-Hua
MH
Wen
Yen-Fang
YF
Yang
Wan-Hsu
WH
Ko
Ching-Huai
CH
Chou
Nien-Tzu
NT
Lin
Mai-Wei
MW
Lai
Chin-Pen
CP
Sun
Chung-Yuan
CY
Wang
Ling-mei
LM
Chen
Yen-Chun
YC
Hseu
Tzong-Hsiung
TH
Chang
Chia-Ni
CN
Hsu
Hui-Chun
HC
Lin
Hui-Chi
HC
Chang
Yu-Li
YL
Shih
Ying-Chu
YC
Chou
Shuen-Hsiang
SH
Hsu
Yi-Ling
YL
Tseng
Hsiang-Wen
HW
Liu
Chih-Peng
CP
Tu
Chia-Mu
CM
Hu
Tsan-Lin
TL
Tsai
Yuan-Jang
YJ
Chen
Ting-Shou
TS
Lin
Chih-Lung
CL
Chiou
Shu-Jiau
SJ
Liu
Chung-Cheng
CC
Hwang
Chrong-Shiong
CS
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D052176:Azulenes / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D052176:Azulenes; C005525:azulene; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3