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Purity: ≥98%
OTSSP167 (OTSSP-167; OTS167; OTS-167) is a highly potent, orally bioavailable inhibitor of MELK (maternal embryonic leucine zipper kinase) with anticancer activity. With an IC50 of 0.41 nM, it blocks MELK. With IC50 values of 6.7, 4.3, 2.3, and 6.0 nM, respectively, OTSSP167 inhibits cancer cells A549, T47D, DU4475, and 22Rv1, in which MELK is highly expressed. The phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which are novel MELK substrates and are critical for stem-cell properties and invasiveness, was inhibited by OTSSP167. Since MELK is upregulated in many types of human tumors, it is thought to be a promising molecular target for cancer therapy. As a result, MELK encourages G2/M transition and EMT in GC while inhibiting apoptosis, which in turn promotes cell growth and invasiveness.
| Targets |
MELK (IC50 = 0.41 nM)
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| ln Vitro |
OTSSP167 blocks MELK-overexpressed cancer cells A549, T47D, DU4475, and 22Rv1 with IC50 values of 6.7, 4.3, 2.3, and 6.0 nM, respectively. OTSSP167 prevented the phosphorylation of two novel MELK substrates, PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which are crucial for stem cell properties and invasiveness. Through the suppression of PSMA1 phosphorylation, OTSSP167 prevents breast cancer cells from forming mammospheres. [1]
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| ln Vivo |
OTSSP167 exhibits significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. OTSSP167 is administered intravenously to the MDA-MB-231 model at a dose of 20 mg/kg once every two days, with a 73% TGI. TGI is 72% when administered orally at a dose of 10 mg/kg once per day. OTSSP167 for various cancer types in a dose- and MELK-dependent manner with little to no body weight loss. [1]
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| Enzyme Assay |
MELK recombinant protein (0.4 μg) is mixed with 5 μg of each substrate in 20 μL of kinase buffer containing 30 mM Tris-HCl (pH), 10 mM DTT, 40 mM NaF, 10 mM MgCl2, 0.1 mM EGTA with 50 μM cold-ATP and 10 Ci of [γ-32P]ATP for 30 min at 30 °C. Prior to SDS-PAGE, the reaction is stopped by adding SDS sample buffer and boiling for 5 minutes. At room temperature, the gel is dried and autoradiographed with intensifying screens. Before the incubation, DMSO-dissolved OTSSP167 (10 nM final concentration) is added to the kinase buffer.
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| Cell Assay |
In vitro cell viability is measured by the colorimetric assay using Cell Counting Kit-8. Cells are plated in 100 μL in 96-well plates at a density that generates continual linear growth (A549, 1×103 cells; T47D, 3×103 cells; DU4475, 4×103 cells; 22Rv1, 6×103 cells; and HT1197, 2×103 cells, in 100 μL per well). The cells are allowed to adhere overnight before exposure to OTSSP167 for 72 hours at 37°C. At a wavelength of 450 nm, a spectrophotometer reads the plates. There are three copies of each assay performed.
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| Animal Protocol |
Injections of MDA-MB-231 cells are made into NOD's mammary fat pads.Mice CB17-Prkdcscid/J. Female BALB/cSLC-nu/nu mice are subcutaneously injected with 1 105 A549), MIAPaCa-2, and PC-14 cells. Male BALB/cSLC-nu/nu mice receive a subcutaneous injection of DU145 cells in the left flank. Animals are randomized into groups of 6 mice (apart from PC-14, for which groups of 3 mice are used) when MDA-MB-231, A549, DU145, MIAPaCa-2, and PC-14 xenografts have reached average volumes of 100, 210, 110, 250, and 250 mm3, respectively. OTSSP167 and other substances are prepared for oral administration in a vehicle containing 0.5% methylcellulose and administered orally according to the prescribed dose and schedule. Compounds are prepared in 5% glucose for intravenous administration and injected into the tail vein. For both administration routes, a volume of 10 mL per kg of body weight is used. Every other day, tumor volumes are measured using a caliper.
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| References |
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| Additional Infomation |
4-[7-acetyl-8-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1H-1,5-naphthyridin-2-ylidene]-2,6-dichloro-1-cyclohexa-2,5-dienone is a naphthyridine derivative.
MELK Inhibitor OTS167 is an orally available inhibitor of maternal embryonic leucine zipper kinase (MELK) with potential antineoplastic activity. Upon administration, OTS167 binds to MELK, which prevents both MELK phosphorylation and activation; thus inhibiting the phosphorylation of downstream MELK substrates. This may lead to an inhibition of both cell proliferation and survival in MELK-expressing tumor cells. MELK, a serine/threonine kinase, is involved in cancer cell survival, invasiveness and cancer-stem cell formation and maintenance; it is highly upregulated in various types of cancer cells and absent in normal, healthy cells. |
| Molecular Formula |
C25H28CL2N4O2
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| Molecular Weight |
487.42
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| Exact Mass |
486.158
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| Elemental Analysis |
C, 61.60; H, 5.79; Cl, 14.55; N, 11.49; O, 6.56
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| CAS # |
1431697-89-0
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| Related CAS # |
OTSSP167 hydrochloride;1431698-10-0
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| PubChem CID |
135398499
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
619.0±55.0 °C at 760 mmHg
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| Flash Point |
328.2±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.644
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| LogP |
6.41
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
648
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC(C2=CC=C(N=CC(C(C)=O)=C3N[C@H]4CC[C@H](CN(C)C)CC4)C3=N2)=CC(Cl)=C1O
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| InChi Key |
DKZYXHCYPUVGAF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H28Cl2N4O2/c1-14(32)18-12-28-22-9-8-21(16-10-19(26)25(33)20(27)11-16)30-24(22)23(18)29-17-6-4-15(5-7-17)13-31(2)3/h8-12,15,17,33H,4-7,13H2,1-3H3,(H,28,29)
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| Chemical Name |
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0516 mL | 10.2581 mL | 20.5162 mL | |
| 5 mM | 0.4103 mL | 2.0516 mL | 4.1032 mL | |
| 10 mM | 0.2052 mL | 1.0258 mL | 2.0516 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02926690 | Recruiting | Drug: OTS167PO | Relapsed/Refractory Locally Advanced or Metastatic Breast Cancer and Triple Negative Breast Cancer |
OncoTherapy Science, Inc. | May 29, 2017 | Phase 1 |
| NCT02768519 | Completed | Drug: OTS167IV Other: Cherry syrup |
Healthy | OncoTherapy Science, Inc. | January 2016 | Phase 1 |
| NCT01910545 | Completed | Drug: OTS167IV | Solid Tumors Metastatic Tumors |
OncoTherapy Science, Inc. | August 23, 2013 | Phase 1 |
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