posted on 2019-04-15, 15:34authored byAli Sohail Farooqi, Jun Young Hong, Ji Cao, Xuan Lu, Ian Robert Price, Qingjie Zhao, Tatsiana Kosciuk, Min Yang, Jessica Jingyi Bai, Hening Lin
Sirtuin 2 (SIRT2)
is a protein lysine deacylase that has been indicated
as a therapeutic target for cancer. To further establish the role
of SIRT2 in cancers, it is necessary to develop selective and potent
inhibitors. Here, we report the facile synthesis of novel lysine-derived
thioureas as mechanism-based SIRT2 inhibitors with anticancer activity.
Compounds AF8, AF10, and AF12 selectively inhibited SIRT2 with IC50 values of 0.06,
0.15, and 0.08 μM, respectively. Compounds AF8 and AF10 demonstrated broad cytotoxicity amongst cancer cell lines,
but minimal toxicity in noncancerous cells. AF8 and AF10 inhibited the anchorage-independent growth of human colorectal
cancer cell line HCT116 with GI50 values of ∼7 μM.
Furthermore, AF8 potently inhibited tumor growth in a
HCT116 xenograft murine model, supporting that SIRT2 is a viable therapeutic
target for colorectal cancer.