OTS964 hydrochloride(cas 1338545-07-5) is a potent TOPK inhibitor with an IC50 value of 28 nM. OTS964 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. OTS964 inhibits 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)].
1. Oncotarget. 2017 Dec 9;9(3):3043-3059. doi: 10.18632/oncotarget.23077. eCollection 2018 Jan 9.
Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations.
Sugimori M(1), Hayakawa Y(2), Koh M(2), Hayashi T(2), Tamura R(1), Kuroda S(2).
(1)Department of Integrative Neuroscience, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan. (2)Department of Neurosurgery, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
Glioblastoma resists chemoradiotherapy, then, recurs to be a fatal space-occupying lesion. The recurrence is caused by re-growing cell populations such as glioma stem cells (GSCs), suggesting that GSC populations should be targeted. This study addressed whether a novel anti-cancer drug, OTS964, an inhibitor for T-LAK cell originated protein kinase (TOPK), is effective in reducing the size of the heterogeneous GSC populations, a power-law coded heterogeneous GSC populations consisting of glioma sphere (GS) clones, by detailing quantitative growth properties. We found that OTS964 killed GS clones while suppressing the growth of surviving GS clones, thus identifying clone-eliminating and growth-disturbing efficacies of OTS964. The efficacies led to a significant size reduction in GS populations in a dose-dependent manner. The surviving GS clones reconstructed GS populations in the following generations; the recovery of GS populations fits a recurrence after the chemotherapy. The recovering GS clones resisted the clone-eliminating effect of OTS964 in sequential exposure during the growth recovery. However, surprisingly, the resistant properties of the recovered-GS clones had been plastically canceled during self-renewal, and then the GS clones had become re-sensitive to OTS964. Thus, OTS964 targets GSCs to eliminate them or suppress their growth, resulting in shrinkage of the power-law coded GSC populations. We propose a therapy focusing on long-term control in recurrence of glioblastoma via reducing the size of the GSC populations by OTS964.