Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 30, Issue 2, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.126807
Keywords
p21-Activated kinase 4; Inhibitor; Thiazolo[4,5-d]pyrimidine; Colorectal cancer
Categories
Funding
- National Natural Science Foundation of China [81230077, 81660587]
- Natural Science Foundation of Inner Mongolia Autonomous region [2016BS0807]
- National Natural Science Foundation of Liaoning province [20170540854]
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Targeting p21-activated kinase 4 (PAK4) is a potential therapeutic strategy against human colorectal cancer (CRC). In this study, we synthesized a series of novel thiazolo [4,5-d]pyrimidine derivatives (PB-1-12) and identified PB-10 (PAK4 IC50 = 15.12 mu M) as a potential and potent PAK4 inhibitor. Our results showed that PB10 significantly suppressed the proliferation and colony formation of human CRC cells. PB-10 also arrested HCT-116 CRC cells at sub G0/G1 phase while promoting the expression of proapoptotic proteins. In addition, PB-10 inhibited migration, invasion, and adhesion as well as the PAK4 downstream signaling pathway in HCT-116 cells. Molecular docking analysis showed possible binding modes between PB-10 and PAK4. Our study provides a novel compound that may block the PAK4 signaling in CRC cells.
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