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Purity: ≥98%
ON123300 is a novel, low molecular weight and potent multikinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. It has minimal inhibitory action against other CDKs like 1, 2, 5, and 8, and inhibits CDK4 with an IC50 of 3.8 nM. PDGFRβ-type platelet-derived growth factor receptor (PDGFRβ) and CDK4, as well as growth factor receptor tyrosine kinases, were all strongly inhibited by ON123300, according to biochemical assays. ON123300 was found to inhibit the proliferation of U87 glioma cells with an IC(50) of 3.4 ± 0.1 μmol/L and to reduce Akt phosphorylation. However, it also surprisingly induced Erk activation in a dose- and time-dependent manner, which was later linked to the relief of Akt-mediated C-Raf S259 inactivation and the activation of a p70S6K-initiated PI3K-negative feedback loop. Since ON123300 showed good pharmacokinetic properties, combinations that reduce its Erk activation and increase its activity—like gefitinib—will likely be needed in its future development as a brain tumor treatment.
| Targets |
Cdk4/cyclin D1 (IC50 = 3.9 nM); ARK5 (IC50 = 5 nM); CDK6/cyclinD1 (IC50 = 9.82 nM); RET (IC50 = 9.2 nM); FYN (IC50 = 11 nM); FGFR1 (IC50 = 26 nM); PDGFRβ (IC50 = 26 nM); PI3K-δ (IC50 = 144 nM)
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| Enzyme Assay |
ON123300 is a newly developed kinase inhibitor that effectively suppresses CDK4/6 and PI3K-δ, demonstrating strong efficacy against MCLs. A series of screens revealed the low molecular weight multi-kinase inhibitor ON123300, which enabled additional research into brain tumor chemotherapy. Based on biochemical assays, ON123300 was found to be a potent inhibitor of growth factor receptor tyrosine kinases, including beta-type platelet-derived growth factor receptor [PDGFRβ], as well as Ark5 and CDK4. With an IC50 = 3.4 ± 0.1 μM, ON123300 suppressed the growth of U87 glioma cells and decreased Akt phosphorylation. However, it also surprisingly activated Erk, both in a dose- and time-dependent way, which was later linked to the relief of Akt-mediated C-Raf S259 inactivation and the induction of a p70S6K-initiated PI3K negative feedback loop.
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| Cell Assay |
ON123300's cytotoxicity is assessed through a colorimetric assay based on sulforhodamine B (SRB). Glioma cell suspensions (100 mL, 2×103 cells) are seeded in 96-well plates and incubated for a whole night to allow the cells to adhere to the plate surface. Next, ON123300 is added to the cells in escalating concentrations for a duration of 72 hours. Following the course of treatment, cells are stained with 0.4% SRB and fixed with 10% (v/v) trichloroacetic acid (TCA). The wavelength at which the optical densities are determined is 570 nm.
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| Animal Protocol |
NIH Swiss nude mice
5 and 25 mg/kg i.v. |
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| References |
| Molecular Formula |
C₂₄H₂₇N₇O
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| Molecular Weight |
429.52
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| Exact Mass |
429.23
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| Elemental Analysis |
C, 67.11; H, 6.34; N, 22.83; O, 3.72
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| CAS # |
1357470-29-1
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| Appearance |
Solid powder
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| SMILES |
CN1CCN(CC1)C2=CC=C(C=C2)NC3=NC=C4C=C(C(=O)N(C4=N3)C5CCCC5)C#N
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| InChi Key |
VADOZMZXXRBXNY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H27N7O/c1-29-10-12-30(13-11-29)20-8-6-19(7-9-20)27-24-26-16-18-14-17(15-25)23(32)31(22(18)28-24)21-4-2-3-5-21/h6-9,14,16,21H,2-5,10-13H2,1H3,(H,26,27,28)
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| Chemical Name |
8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile
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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: 5 mg/mL (11.64 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 | 2.3282 mL | 11.6409 mL | 23.2818 mL | |
| 5 mM | 0.4656 mL | 2.3282 mL | 4.6564 mL | |
| 10 mM | 0.2328 mL | 1.1641 mL | 2.3282 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 | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04739293 | Recruiting | Drug: ON123300 | Solid Tumors, Adult | Onconova Therapeutics, Inc. | May 13, 2021 | Phase 1 |
| NCT05705505 | Recruiting | Drug: Narazaciclib Drug: Letrozole 2.5mg |
Endometrioid Endometrial Cancer | Onconova Therapeutics, Inc. | March 29, 2023 | Phase 1 Phase 2 |
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