Background:

OTS964{(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c] quinolin-4(5H)-one} is a potent TOPK inhibitor with an IC50 value of 28 nM. It is a dimethylated derivative of OTS514. OTS964 can inhibit TOPK kinase activity with high affinity and selectivity. TOPK (T-lymphokine-activated killer cell-originated protein kinase) is a protein that is found in a wide range of human cancers and is believed to work as an oncogene, promoting tumor growth.

It has been reported that OTS964 inhibited the growth of TOPK-positive cells with low IC50 values [A549 (31 nM), LU-99 (7.6 nM), DU4475 (53 nM), MDA-MB-231 (73 nM), T47D (72 nM), Daudi (25 nM), UM-UC-3 (32 nM), HCT-116(33nM), MKN1(38nM), MKN45(39nM), HepG2(19nM), MIAPaca-2 (30 nM), and 22Rv1 (50 nM)]. However, its growth inhibitory effect against TOPK-negative HT29 cancer cells was significantly weaker, with IC50 value of 290 nM. Intravenous administration of OTS964 at 40 mg/kg on days 1, 4, 8, 11, 15, and 18 to mice bearing LU-99 lung cancer cells, a TGI of 44% was observed on day 22 without any body weight loss. The differentiation of HSCs to amega-karyocyte population was also enhanced by OTS964 treatment¹.

参考文献:
1. Matsuo Y, Park JH2, Miyamoto T, et al. TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis. ci Transl Med. 2014 Oct 22;6(259):259ra145.