OTS964TOPK inhibitor,potent and selective CAS# 1338545-07-5 |
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Quality Control & MSDS
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Chemical structure
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| Cas No. | 1338545-07-5 | SDF | Download SDF |
| PubChem ID | 67449676 | Appearance | Powder |
| Formula | C22H22N2O2S | M.Wt | 378.49 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 83.33 mg/mL (194.26 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 9-[4-[(2R)-1-(dimethylamino)propan-2-yl]phenyl]-8-hydroxy-5H-thieno[2,3-c]quinolin-4-one | ||
| SMILES | CC(CN(C)C)C1=CC=C(C=C1)C2=C(C=CC3=C2C4=C(C(=O)N3)SC=C4)O | ||
| Standard InChIKey | WGYWHJPQFQGLOQ-ZDUSSCGKSA-N | ||
| Standard InChI | InChI=1S/C22H22N2O2S/c1-13(12-24(2)3)14-4-6-15(7-5-14)19-18(25)9-8-17-20(19)16-10-11-27-21(16)22(26)23-17/h4-11,13,25H,12H2,1-3H3,(H,23,26)/t13-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | OTS-964 is a potent TOPK inhibitor (IC50=28 nM), which inhibits TOPK kinase activity with high affinity and selectivity.In Vitro:OTS-964 (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 (33 nM), MKN1 (38 nM), MKN45 (39 nM), HepG2 (19 nM), MIAPaca-2 (30 nM), and 22Rv1 (50 nM)], whereas its growth inhibitory effect against TOPK-negative HT29 cancer cells is significantly (P=1.45×10-4) weaker, with IC50 of 290 nM. Although OTS-964 reveals some suppressive effect on Src family kinases, the response to OTS-964 in these cancer cells is not correlated with the expression of Src family kinases c-Src, Fyn, and Lyn. Treatment with OTS-964 decreases autophosphorylation of TOPK (Thr9), as well as phosphorylation of histone H3 (Ser10), in both T47D and LU-99 cells. Moreover, time lapse imaging in T47D cells shows that treatment with OTS-964 induces cytokinesis defects followed by apoptosis, which is not observed in control DMSO-treated T47D cells[1].In Vivo:Three LU-99 xenograft mice are intravenously treated with liposomal OTS-964 (40 mg/kg) or vehicle at days 1, 4, 8, and 11, and tumors are collected on day 12. The cellular morphological changes and apoptosis are examined t in the LU-99 cells. Treatment with OTS-964 induced irregular cell morphology with cytokinesis defects. Treatment with OTS-964 significantly increases the number of LU-99 cells with the “intercellular bridge” (P<0.0001), which is one of the markers indicating impaired cell division. The oral administration of free OTS-964 at 50 or 100 mg/kg once every day for 2 weeks results in TGIs of 79 and 113% on day 15, respectively, without any body weight loss. Similar to the intravenous administration of liposomal OTS-964, cell morphological changes, inhibition of TOPK activity, and increased cancer cell death are observed after oral administration of OTS-964 for 1 week. In the 100 mg/kg dosing group, continuous tumor shrinkage is observed after the final administration of the drug, and all six of the mice achieve complete tumor regression (one on day 22, three on day 25, and two on day 29)[1]. References: | |||||
| Cell experiment [2]: | |
| Cell lines | AML-CD34+, MV4-11 and MOLM13 cell lines |
| Preparation method | Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
| Reacting condition | ~ 48 hours |
| Applications | There is a significant decrease in the number of colonies per well in AML-CD34+ cells treated with 10 nM of OTS514 compared to untreated cells (41 vs 73, P = 0.01). OTS514 exhibits cytotoxic activity in AML cells but not in normal CD34+ cells. OTS514 also leads to 80% and 70% increase in apoptotic cell population in MV4-11 and MOLM13 cells that carried FLT3 mutations. |
| Animal experiment [1]: | |
| Animal models | LU-99 xenografts (female BALB/cSLC-nu/nu Mice) |
| Dosage form | Intravenously treated with liposomal OTS964 (40 mg/kg) |
| Application | OTS514 induces irregular cell morphology with cytokinesis defects and significantly increases the number of LU-99 cells with the “intercellular bridge” which is one of the markers indicating impaired cell division. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: 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. 2. Alachkar H, Mutonga M, Malnassy G et al. T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia. Oncotarget. 2015 Oct 20;6(32):33410-25. | |
OTS964 Dilution Calculator
OTS964 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.6421 mL | 13.2104 mL | 26.4208 mL | 52.8416 mL | 66.0519 mL |
| 5 mM | 0.5284 mL | 2.6421 mL | 5.2842 mL | 10.5683 mL | 13.2104 mL |
| 10 mM | 0.2642 mL | 1.321 mL | 2.6421 mL | 5.2842 mL | 6.6052 mL |
| 50 mM | 0.0528 mL | 0.2642 mL | 0.5284 mL | 1.0568 mL | 1.321 mL |
| 100 mM | 0.0264 mL | 0.1321 mL | 0.2642 mL | 0.5284 mL | 0.6605 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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 treatment 1.
References:
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.
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TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis.[Pubmed:25338756]
Sci Transl Med. 2014 Oct 22;6(259):259ra145.
TOPK (T-lymphokine-activated killer cell-originated protein kinase) is highly and frequently transactivated in various cancer tissues, including lung and triple-negative breast cancers, and plays an indispensable role in the mitosis of cancer cells. We report the development of a potent TOPK inhibitor, OTS964 {(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]qu inolin-4(5H)-one}, which inhibits TOPK kinase activity with high affinity and selectivity. Similar to the knockdown effect of TOPK small interfering RNAs (siRNAs), this inhibitor causes a cytokinesis defect and the subsequent apoptosis of cancer cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. Our results suggest that the inhibition of TOPK activity may be a viable therapeutic option for the treatment of various human cancers.
T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer.[Pubmed:27334838]
Clin Cancer Res. 2016 Dec 15;22(24):6110-6117.
BACKGROUND: We aimed to clarify the clinical significance of TOPK (T-lymphokine-activated killer cell-originated protein kinase) expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells. METHODS: TOPK expression was examined by immunohistochemistry using 163 samples with epithelial ovarian cancer (EOC). TOPK protein level and FOXM1 transcriptional level in ovarian cancer cell lines were examined by Western blot and RT-PCR, respectively. Half-maximum inhibitory concentration (IC50) values against TOPK inhibitors were examined by the MTT assay. Using the peritoneal dissemination model of ES-2 ovarian cancer cells, we examined the in vivo efficacy of OTS514. In addition, the cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined. RESULTS: TOPK was expressed very highly in 84 (52%) of 163 EOC tissues, and high TOPK expression was significantly associated with poor progression-free survival and overall survival in early-stage cases of EOC (P = 0.008 and 0.006, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on ovarian cancer cell lines with IC50 values of 3.0 to 46 nmol/L and 14 to 110 nmol/L, respectively. TOPK protein and transcriptional levels of FOXM1 were reduced by TOPK inhibitor treatment. Oral administration of OTS514 significantly elongated overall survival in the ES-2 abdominal dissemination xenograft model, compared with vehicle control (P < 0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless of tumor sites or histological subtypes. CONCLUSIONS: Our results demonstrated the clinical significance of high TOPK expression and potential of TOPK inhibitors to treat ovarian cancer. Clin Cancer Res; 22(24); 6110-7. (c)2016 AACR.
Novel molecule targets cytokinesis.[Pubmed:25583820]
Cancer Discov. 2015 Jan;5(1):OF8.
Researchers have identified a new compound, OTS964, that blocks cytokinesis. Injections of the compound eliminated human lung tumors that had been transplanted into mice. Clinical trials of OTS964 may start next year.
TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy.[Pubmed:28677687]
Br J Cancer. 2017 Aug 8;117(4):503-512.
BACKGROUND: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. METHODS: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. RESULTS: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G1/S transition and G2/M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. CONCLUSIONS: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.
