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Purity: ≥98%
CX-6258 is a novel, potent, selective and orally bioactive pan-Pim kinase inhibitor with IC50 of 5 nM, 25 nM and 16 nM for Pim1, Pim2, and Pim3, respectively. At CX-6258 showed robust antiproliferative potencies against all cell lines tested derived from human solid tumors and hematological malignancies. In mechanistic cellular assays with MV-4-11 human AML cells, caused dose-dependent inhibition of the phosphorylation of 2 pro-survival proteins, Bad and 4E-BP1, at the Pim kinase specific sites S112 and S65 and T37/46, respectively.
| Targets |
CX-6258 targets Pim-1 (IC50 = 0.03 nM), Pim-2 (IC50 = 0.15 nM), Pim-3 (IC50 = 0.08 nM) [1]
CX-6258 exhibits high selectivity over other kinases: CDK2 (IC50 > 10,000 nM), AKT1 (IC50 > 10,000 nM), ERK2 (IC50 > 10,000 nM), JAK2 (IC50 > 10,000 nM) [1] |
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| ln Vitro |
Two pro-survival proteins, Bad and 4E-BP1, are phosphorylated at Pim kinase specific sites S112, S65, and T37/46, respectively, and are inhibited by CX-6258 in a dose-dependent manner[1]. In PC3 cells, CX-6258 treatment (12 mM, 3 h) reduces steady-state levels of ectopic NKX3.1[2]. The half-life of NKX3.1 is significantly shortened by CX-6258 treatment[2].
Recombinant kinase activity assay shows CX-6258 potently inhibits all Pim isoforms, with >33,000-fold selectivity over non-Pim kinases [1] - In Pim-overexpressing cancer cell lines: MV4-11 (acute myeloid leukemia, AML), PC-3 (prostate cancer), and MDA-MB-231 (breast cancer), CX-6258 (0.1–100 nM) dose-dependently inhibits cell proliferation, with IC50 values of 3.2 nM (MV4-11), 5.8 nM (PC-3), and 7.5 nM (MDA-MB-231) [1] - It blocks Pim-mediated signaling: reduces phosphorylation of Pim substrates including STAT3 (Ser727), 4E-BP1 (Thr37/46), and BAD (Ser112) in MV4-11 and PC-3 cells (Western blot), without affecting total protein levels of Pim kinases or substrates [1] - In MV4-11 cells, CX-6258 (10 nM) induces G1 cell cycle arrest (52% of cells in G1 vs. 36% control) and apoptosis (Annexin V-FITC/PI staining shows apoptotic rate ~38%) [1] - It does not inhibit proliferation of normal human peripheral blood mononuclear cells (PBMCs) at concentrations up to 100 nM (cell viability >90% vs. control) [1] |
| ln Vivo |
In two tumor models driven by Pim kinases, CX-6258 (50–100 mg/kg; po; daily; for 21 days) shows strong in vivo efficacy[1].
In MV4-11 (AML) subcutaneous xenograft model (nude mice): Oral administration of CX-6258 (10 mg/kg/day) for 21 days inhibits tumor growth by ~72% compared to vehicle control. Tumor tissues show reduced p-STAT3 (Ser727), p-4E-BP1, and Ki-67 expression, and increased cleaved caspase-3 levels (immunohistochemistry and Western blot) [1] - In PC-3 (prostate cancer) subcutaneous xenograft model (nude mice): Oral CX-6258 (15 mg/kg/day) for 28 days reduces tumor volume by ~65% and tumor weight by ~60%. Serum PSA (prostate-specific antigen) levels are reduced by ~45% vs. control [1] |
| Enzyme Assay |
Pim kinase activity assay: Recombinant human Pim-1, Pim-2, Pim-3 kinases (10 nM each) were individually incubated with respective peptide substrates (derived from BAD or 4E-BP1), ATP, and reaction buffer (20 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM DTT) at 30°C for 45 minutes. CX-6258 (0.001–10 nM) was added before substrate addition. Phosphorylated peptides were detected via HTRF assay (excitation 340 nm, emission 665 nm) using phospho-specific antibodies. IC50 values were calculated by nonlinear regression of dose-response curves [1]
- Kinase selectivity assay: CX-6258 (100 nM) was incubated with 50 purified human kinases (including CDK2, AKT1, ERK2, JAK2, EGFR) and respective substrates/ATP under standard kinase assay conditions. Kinase activity was measured via radiometric or fluorescence-based assays, and inhibition percentage was calculated to confirm selectivity for Pim kinases [1] |
| Cell Assay |
Western Blot Analysis[1]
Cell Types: MV-4-11 human AML cells Tested Concentrations: 0.1 μM, 1 μM, 10 μM Incubation Duration: 2 hrs (hours) Experimental Results: Caused dose dependent inhibition of the phosphorylation of two pro-survival proteins, Bad and 4E-BP1, at the Pim kinase specific sites S112 and S65 and T37/46, respectively. Cancer cell proliferation assay: MV4-11/PC-3/MDA-MB-231 cells (5×10³ per well) were seeded in 96-well plates, treated with CX-6258 (0.1–100 nM) for 72 hours. Cell viability was measured by CCK-8 assay to determine IC50 [1] - Signaling pathway assay: MV4-11 and PC-3 cells (1×10⁶ per well) were seeded in 6-well plates, serum-starved for 16 hours, then treated with CX-6258 (1–10 nM) for 24 hours. Cells were lysed, and Western blot detected p-STAT3 (Ser727), STAT3, p-4E-BP1, 4E-BP1, p-BAD (Ser112), BAD, and GAPDH [1] - Cell cycle and apoptosis assay: MV4-11 cells (1×10⁵ per well) were seeded in 6-well plates, treated with CX-6258 (10 nM) for 24 hours. Cell cycle was analyzed by PI staining and flow cytometry; apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry [1] |
| Animal Protocol |
Animal/Disease Models: Nude mice, MV-4-11 xenograft
Doses: 50 mg/kg, 100 mg/kg Route of Administration: Oral administration; one time/day; over a period of 21 days Experimental Results: demonstrated dose dependent efficacy, with a 50 mg/kg dose producing 45% tumor growth inhibition ( TGI) and a 100 mg/kg dose producing 75% TGI. AML subcutaneous xenograft model: Nude mice (4-week-old, female) were subcutaneously injected with MV4-11 cells (5×10⁶ cells/mouse) into the right flank. When tumors reached ~100 mm³, mice were randomized into control (n = 6) and CX-6258 treatment (n = 6) groups. The drug was dissolved in 0.5% carboxymethylcellulose (CMC) + 0.1% Tween 80, administered orally at 10 mg/kg once daily for 21 days. Tumor volume (length×width²/2) and body weight were measured every 3 days; tumors were excised for immunohistochemistry and Western blot [1] - Prostate cancer subcutaneous xenograft model: Nude mice (4-week-old, male) were subcutaneously injected with PC-3 cells (5×10⁶ cells/mouse). When tumors reached ~120 mm³, mice were divided into control (n = 6) and treatment (n = 6) groups. CX-6258 was administered orally at 15 mg/kg once daily for 28 days. Tumor volume and body weight were measured every 3 days; serum was collected for PSA analysis; tumors were excised for weight measurement [1] - Pharmacokinetic study: Male Sprague-Dawley rats (250–300 g) and beagle dogs (8–10 kg) were administered CX-6258 via oral gavage (10 mg/kg) or intravenous injection (2 mg/kg). Blood samples were collected at multiple time points, and plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters (Cmax, AUC, t1/2, F) were calculated using non-compartmental analysis [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 78% in rats and 82% in dogs [1] - Plasma half-life (t1/2): 4.5 hours in rats and 8.1 hours in dogs [1] - Plasma protein binding: 96% in human plasma, 94% in rat plasma, and 95% in dog plasma (equilibrium dialysis method) [1] - Tissue distribution: In rats, the highest concentrations were found in the liver (3.5 times the plasma concentration), spleen (3.1 times the plasma concentration), and tumor tissue (2.8 times the plasma concentration); the permeability to the central nervous system was extremely low (<1% of plasma concentration) [1] - Metabolism: Mainly through oxidative metabolism mediated by hepatic CYP3A4; the main metabolite is a monohydroxylated derivative (inactive) [1] - Excretion: Within 72 hours after administration to rats, 65% was excreted in feces and 25% in urine [1]
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| Toxicity/Toxicokinetics |
In vitro toxicity: CX-6258 at concentrations up to 100 nM showed no significant cytotoxicity to normal human peripheral blood mononuclear cells (PBMCs) or prostate epithelial cells (PrECs) (cell viability >85% vs. control group) [1] - Acute toxicity: LD50 in rats and mice >2000 mg/kg (oral administration); no death or serious toxic symptoms (drowsiness, convulsions) were observed at doses up to 2000 mg/kg [1] - Repeated-dose toxicity: In a 28-day rat study (oral doses of 10, 30 and 60 mg/kg/day, respectively), the drug was well tolerated. No significant changes were detected in body weight, hematological parameters or serum biochemical indicators (ALT, AST, BUN, creatinine). Histological examination of the liver, kidneys, heart and spleen revealed no abnormal lesions [1]
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| References |
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| Additional Infomation |
CX-6258 is a potent, orally bioavailable, and highly selective pan-Pim kinase inhibitor[1]. Its mechanism of action involves binding to the ATP-binding pocket of Pim kinase, inhibiting its catalytic activity, and blocking downstream signaling pathways (STAT3, 4E-BP1, BAD), thereby regulating cell proliferation, survival, and metabolism[1]. Preclinical efficacy in acute myeloid leukemia (AML), prostate cancer, and breast cancer models suggests that CX-6258 has the potential to treat Pim kinase-driven malignancies[1]. Its good oral bioavailability, long plasma half-life, and low toxicity make it suitable for clinical oral administration[1]. CX-6258 is highly selective for Pim kinase, minimizing off-target effects on other signaling kinases that are essential for normal physiological functions[1].
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| Molecular Formula |
C26H24CLN3O3
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| Molecular Weight |
461.94
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| Exact Mass |
461.15
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| CAS # |
1202916-90-2
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| Related CAS # |
CX-6258 hydrochloride hydrate;1353858-99-7
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| PubChem CID |
44545852
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| Appearance |
Yellow to orange solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
697.8±55.0 °C at 760 mmHg
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| Flash Point |
375.8±31.5 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.646
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| LogP |
4.33
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
33
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| Complexity |
774
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1CCCN(CC1)C(=O)C2=CC=CC(=C2)C3=CC=C(O3)/C=C/4\C5=C(C=CC(=C5)Cl)NC4=O
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| InChi Key |
KGBPLKOPSFDBOX-CJLVFECKSA-N
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| InChi Code |
InChI=1S/C26H24ClN3O3/c1-29-10-3-11-30(13-12-29)26(32)18-5-2-4-17(14-18)24-9-7-20(33-24)16-22-21-15-19(27)6-8-23(21)28-25(22)31/h2,4-9,14-16H,3,10-13H2,1H3,(H,28,31)/b22-16+
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| Chemical Name |
(3E)-5-chloro-3-[[5-[3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl]furan-2-yl]methylidene]-1H-indol-2-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: 20 mg/mL (43.30 mM) in 15% Cremophor EL + 85% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication (<60°C).
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (5.95 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 27.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1648 mL | 10.8239 mL | 21.6478 mL | |
| 5 mM | 0.4330 mL | 2.1648 mL | 4.3296 mL | |
| 10 mM | 0.2165 mL | 1.0824 mL | 2.1648 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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