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Purity: ≥98%
XMD8-92 (XMD-8-92) is a novel, potent and highly selective dual inhibitor of BMK1/ERK5 (big mitogen activated protein kinase 1 / extracellular-signal-regulated kinase) with potential antineoplastic activity. It has a Kd of 80 nM to inhibit BMK1/ERK5 and Kds of 190, 890, and 600 nM, respectively, to inhibit DCAMKL2, TNK1, and Plk4, respectively. It exhibits significant in vivo antitumor efficacy in a pancreatic tumor xenograft model and potent anti-proliferative activity in vitro through a DCLK1-dependent mechanism. Transcriptional factors necessary for human myeloid leukemia cells to differentiate into monocytic cells are regulated by the ERK5 pathway. The most recent and least researched mammalian mitogen-activated protein (MAP) kinase cascade that has been discovered so far is the big mitogen activated protein kinase 1 (BMK1) pathway. It is widely expressed in all types of cancer cells that have been examined so far. To transmit proliferative, survival, chemoresistance, invasive, and angiogenic signals to tumor cells, mitogens and oncogenic signals must first strongly activate this cellular MAP kinase pathway.
| Targets |
BMK1 (Kd = 80 nM); BMK1 (Kd = 190 nM)
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| ln Vitro |
XMD8-92 significantly increases p21 expression in cells and inhibits the proliferation of cancer cells by inhibiting BMK1 activation.[1] In addition to blocking the down-regulation of MEF2C caused by hydroxysafflor yellow A (HSYA), XMD8-92 also significantly reduces the inhibitory effects of HSYA on the activation of hepatic stellate cells (HSCs).[2]
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| ln Vivo |
XMD8-92 (50 mg/kg i.p.) significantly slows the growth of xenografted human or syngeneic mouse tumors by preventing tumor cell proliferation and tumor-associated angiogenesis.[1] XMD8-92 significantly downregulates DCLK1 and several of its downstream targets, which prevents pancreatic tumor xenograft growth.[3]
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| Enzyme Assay |
The following modifications are made when performing KiNativ profiling on XMD8-92 using an ATP and ADP acylphosphate-desthiobiotin. Prior to adding the ATP or ADP acylphosphate probe (5 μM final probe concentration), HeLa cell lysates (total protein concentration: 5 mg/mL) are incubated with XMD8-92 at 50 μM, 10 μM, 2 μM, 0.8 μM, and 0 μM for 15 minutes. A duplicate of each reaction is carried out. Probe reactions continued for 10 minutes before being processed for MS analysis and stopping when urea was added. In order to collect MS/MS spectra from all kinase peptide-probe conjugates that can be found in HeLa cell lysates, samples are analyzed by LC-MS/MS on a linear ion trap mass spectrometer using a time-segmented "target list." This target list was created and verified through a thorough analysis of HeLa lysates in the past. A comparison of inhibitor-treated to control (untreated) lysates allows for the precise determination of% inhibition at each point. Up to four characteristic fragment ions for each kinase peptide-probe conjugate are used to extract signals for each kinase. The specifics of this targeted mass spectrometry strategy will be covered in a manuscript that is currently being written.
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| Animal Protocol |
Nod/Scid mice bearing HeLa xenograft, C57Bl/6 mice bearing LL/2 xenograft
~50 mg/kg twice a day i.p. |
| References | |
| Additional Infomation |
XMD8-92 is a dimethylpyrimido[4,5-b][1,4]benzodiazepin-6-one carrying at C-2 on the pyrimidine ring a [2-ethoxy-4-(4-hydroxypiperidin-1-yl)phenyl]amino substituent. It is an inhibitor of the BMK1 kinase pathway. It has a role as a protein kinase inhibitor.
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| Molecular Formula |
C26H30N6O3
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|---|---|---|
| Molecular Weight |
474.55
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| Exact Mass |
474.237
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| Elemental Analysis |
C, 65.80; H, 6.37; N, 17.71; O, 10.11
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| CAS # |
1234480-50-2
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| Related CAS # |
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| PubChem CID |
46843772
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| Appearance |
White to beige solid powder.
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
741.8±70.0 °C at 760 mmHg
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| Flash Point |
402.4±35.7 °C
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| Vapour Pressure |
0.0±2.6 mmHg at 25°C
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| Index of Refraction |
1.655
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| LogP |
1.14
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
35
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| Complexity |
719
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O([H])C1([H])C([H])([H])C([H])([H])N(C2C([H])=C([H])C(=C(C=2[H])OC([H])([H])C([H])([H])[H])N([H])C2=NC([H])=C3C(=N2)N(C([H])([H])[H])C2=C([H])C([H])=C([H])C([H])=C2C(N3C([H])([H])[H])=O)C([H])([H])C1([H])[H]
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| InChi Key |
QAPAJIZPZGWAND-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H30N6O3/c1-4-35-23-15-17(32-13-11-18(33)12-14-32)9-10-20(23)28-26-27-16-22-24(29-26)30(2)21-8-6-5-7-19(21)25(34)31(22)3/h5-10,15-16,18,33H,4,11-14H2,1-3H3,(H,27,28,29)
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| Chemical Name |
2-[2-ethoxy-4-(4-hydroxypiperidin-1-yl)anilino]-5,11-dimethylpyrimido[4,5-b][1,4]benzodiazepin-6-one
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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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1073 mL | 10.5363 mL | 21.0726 mL | |
| 5 mM | 0.4215 mL | 2.1073 mL | 4.2145 mL | |
| 10 mM | 0.2107 mL | 1.0536 mL | 2.1073 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.
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