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Purity: ≥98%
JNJ-47117096 HCl (also known as MELK-T1), identified from a fragment-based drug design, is a novel, potent and selective MELK (maternal embryonic leucine zipper kinase) inhibitor with an IC50 of 23 nM, it also effectively inhibits Flt3, with an IC50 of 18 nM. Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold.
| ln Vitro |
JNJ-47117096 hydrochloride has an IC50 of 23 nM, making it a strong and selective MELK inhibitor. Additionally, it blocks Flt3 effectively (IC50 = 18 nM), and it blocks CAMKIIδ, Mnk2, CAMKIIγ, and MLCK (IC50 = 810 nM, 760 nM, 1000 nm, 1000 nm). In the absence of IL-3, JNJ-47117096 (MELK-T1) suppresses Flt3-driven proliferation of the Ba/F3 cell line with an IC50 of 1.5 μM; in the presence of IL-3, no inhibitory effect was detected. Regardless of the presence or absence of IL-3, JNJ-47117096 did not impede the growth of Ba/F3 cell lines transfected with FGFR1, FGFR3, or KDR [1]. MCF-7 cells' entry into the S phase can be postponed by JNJ-47117096 (MELK-T1, 10 μM). MELK is inhibited by JNJ-47117096, leading to replication fork stalling and DNA double-strand breaks (DSBs). The ATM-mediated DNA damage response is activated by JNJ-47117096 (DDR). Growth arrest and senescence characteristics are brought on by JNJ-47117096 (3, 10 μM). Furthermore, JNJ-47117096 causes long-term overexpression of p21, significant phosphorylation of p53, and downregulation of FOXM1 target genes [2].
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| References |
[1]. Johnson CN, et al. Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase. ACS Med Chem Lett. 2014 May 23;6(1):25-30.
[2]. Beke L, et al. MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells. Biosci Rep. 2015 Oct 2;35(6). pii: e00267 |
| Molecular Formula |
C21H23CLN4O2
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| Molecular Weight |
398.885923624039
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| CAS # |
1610536-69-0
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| Related CAS # |
1610536-69-0 (HCl);1610586-62-3;
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| SMILES |
O=C(NC1=CC=C2CCNCCC2=C1)C3=CC=C(C4=CNN=C4)C=C3OC.Cl
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| Synonyms |
JNJ-47117096 hydrochloride; JNJ 47117096 hydrochloride; JNJ47117096 hydrochloride; JNJ-47117096; JNJ-47117096 HCl; MELK T1; MELK-T1 HCl; MELK-T1
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
DMSO : ≥ 250 mg/mL (~626.74 mM)
H2O : ~3.33 mg/mL (~8.35 mM) |
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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 | 2.5070 mL | 12.5348 mL | 25.0696 mL | |
| 5 mM | 0.5014 mL | 2.5070 mL | 5.0139 mL | |
| 10 mM | 0.2507 mL | 1.2535 mL | 2.5070 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.
 Inhibition of MELK by MELK-T1 (JNJ-47117096).Biosci Rep.2015 Oct 2;35(6). pii: e00267. |
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 MELK-T1 triggers the proteasome-mediated degradation of MELK protein.
MELK-T1 induces a delay in the progression of MCF-7 cells through S-phase.Biosci Rep.2015 Oct 2;35(6). pii: e00267. |
 Effects of MELK-T1 on DNA structure and replication.
Model of how MELK increases the DDT barrier.Biosci Rep.2015 Oct 2;35(6). pii: e00267. |
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