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Purity: ≥98%
XMD8-87 (also known as ACK1-B19) is a novel tyrosine kinase nonreceptor 2(TNK2) inhibitor with IC50s of 38 nmol/L and 113 nmol/L for the D163E and R806Q mutations. XMD8-87 has been reported to be potent in the inhibition of TNK2 phosphorylation. XMD8-87 and XMD16-5 potently inhibit phosphorylation of TNK2 truncation mutations found in solid tumor types. XMD8-87 was identified from kinase inhibitor screens to predict functional gene targets in primary specimens from patients with acute myeloid leukemia and chronic myelomonocytic leukemia. Deep sequencing of the same patient specimens identified genetic alterations that were then integrated with the functionally important targets using the HitWalker algorithm to prioritize the mutant genes that most likely explain the observed drug sensitivity patterns.
| Targets |
Tyrosine Kinase Nonreceptor 2 (TNK2/ACK1) (Ki = 1.2 nM; IC50 = 3.5 nM for kinase activity) [1]
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| ln Vitro |
Even at the highest tested dosages (1,000 nM), XMD8-87 has little to no effect on control cells but potently suppresses the development of TNK2 mutant expressing cell lines. For the D163E and R806Q mutations, XMD8-87's IC50 values are 38 nM and 113 nM, respectively. On-target effects on TNK2 account for the majority of XMD8-87's effects on TNK2 cell lines. TNK2 inhibitor XMD8-87 may prevent overexpressed TNK2 mutants from auto-phosphorylating[1].
XMD8-87 (ACK1-B19) is a potent and selective inhibitor of ACK1 (TNK2) kinase. It competitively binds to the ATP-binding pocket of ACK1 with a Ki of 1.2 nM, and inhibits recombinant ACK1 kinase activity with an IC50 of 3.5 nM [1] - In human leukemia cell lines harboring TNK2 mutations (MOLM-13, MV4-11), XMD8-87 (0.5–20 μM) dose-dependently inhibits cell proliferation. At 5 μM, it reduces MOLM-13 cell viability by 62% after 72 h treatment, and induces G2/M phase cell cycle arrest (G2/M cells increased from 18% to 43%) [1] - XMD8-87 (2–10 μM) dose-dependently reduces phosphorylated ACK1 (p-ACK1, Tyr284) levels in MOLM-13 cells, with a 75% reduction at 10 μM. It also inhibits downstream AKT phosphorylation (p-AKT Ser473 reduced by 58% at 5 μM) and STAT3 activation (p-STAT3 Tyr705 reduced by 61% at 5 μM) [1] - It shows minimal activity against other kinases (e.g., EGFR, SRC, ABLC) with IC50 values >1000 nM, confirming high selectivity for ACK1 [1] - In primary leukemia cells from patients with TNK2 mutations, XMD8-87 (10 μM) inhibits cell proliferation by 53% and reduces p-ACK1 levels by 68% compared to vehicle control [1] |
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| ln Vivo |
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| Enzyme Assay |
ACK1 kinase activity assay: Recombinant human ACK1 catalytic domain was incubated with a fluorescently labeled peptide substrate (derived from ACK1 substrate), ATP (10 μM, with [γ-32P]-ATP as tracer), and serial concentrations of XMD8-87 (0.01–50 nM) at 30°C for 40 minutes. The reaction was terminated by adding phosphoric acid, and the mixture was spotted onto a P81 phosphocellulose paper. Unbound radioactivity was washed away, and the paper was counted by liquid scintillation to quantify phosphorylated substrate. IC50 and Ki values were calculated from dose-response curves and competitive binding analysis [1]
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| Cell Assay |
Leukemia cell proliferation assay: MOLM-13 and MV4-11 cells were seeded in 96-well plates (5×103 cells/well) and cultured for 24 hours. Serial concentrations of XMD8-87 (0.1–50 μM) were added, and cells were cultured for another 72 hours. Cell viability was assessed by CCK-8 assay (absorbance at 450 nm), and IC50 values were derived from dose-response curves [1]
- Cell cycle analysis: MOLM-13 cells were treated with XMD8-87 (5 μM) for 48 hours. Cells were harvested, fixed with 70% ethanol, stained with propidium iodide, and analyzed by flow cytometry to determine cell cycle distribution [1] - Western blot analysis: MOLM-13 cells were treated with XMD8-87 (2–10 μM) for 24 hours, then lysed in RIPA buffer containing protease and phosphatase inhibitors. Proteins were separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against p-ACK1 (Tyr284), ACK1, p-AKT (Ser473), AKT, p-STAT3 (Tyr705), STAT3, and β-actin. Band intensity was quantified by densitometry [1] - Primary leukemia cell assay: Primary cells were isolated from bone marrow of patients with TNK2-mutated leukemia, seeded in 24-well plates (1×105 cells/well) in serum-free medium, and treated with XMD8-87 (10 μM) for 72 hours. Cell proliferation was measured by trypan blue exclusion assay, and p-ACK1 levels were detected by Western blot [1] |
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| Additional Infomation |
XMD8-87 (ACK1-B19) is a small-molecule selective tyrosine kinase non-receptor 2 (TNK2/ACK1) inhibitor, discovered through kinase inhibitor screening combined with genomic analysis of leukemia samples [1]. Its mechanism of action is to competitively bind to the ATP-binding pocket of ACK1, inhibiting its kinase activity and blocking downstream signaling pathways (AKT/STAT3) that promote the proliferation and survival of leukemia cells [1]. XMD8-87 has preferential activity against leukemia cells carrying TNK2 mutations, making it a potential targeted therapy for TNK2-mutant leukemia, a type of hematologic malignancy with limited treatment options [1]. The drug’s high selectivity for ACK1 minimizes off-target effects on other kinases, thereby reducing potential cytotoxicity to normal cells [1].
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| Molecular Formula |
C24H27N7O2
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| Molecular Weight |
445.52
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| Exact Mass |
445.222
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| CAS # |
1234480-46-6
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| Related CAS # |
1234480-46-6;1321828-64-1 (TFA);
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| PubChem CID |
53322923
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| Appearance |
White to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.648
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| LogP |
1.23
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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 |
4
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| Heavy Atom Count |
33
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| Complexity |
673
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LGLHCXISMKHLIK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H27N7O2/c1-29-10-12-31(13-11-29)16-8-9-18(21(14-16)33-3)27-24-25-15-19-22(28-24)30(2)20-7-5-4-6-17(20)23(32)26-19/h4-9,14-15H,10-13H2,1-3H3,(H,26,32)(H,25,27,28)
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| Chemical Name |
2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-11-methyl-5H-pyrimido[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: ≥ 2.08 mg/mL (4.67 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 20.8 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: 2.08 mg/mL (4.67 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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 | 2.2446 mL | 11.2228 mL | 22.4457 mL | |
| 5 mM | 0.4489 mL | 2.2446 mL | 4.4891 mL | |
| 10 mM | 0.2245 mL | 1.1223 mL | 2.2446 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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