1357470-29-1

Basic information

• Product Name: ON123300
• Synonyms: ON123300;8-Cyclopentyl-7,8-dihydro-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-7-oxo-pyrido[2,3-d]pyrimidine-6-carbonitrile;123300;ON-​8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
• CAS NO: 1357470-29-1
• Molecular Formula: C₂₄H₂₇N₇O
• Molecular Weight: 429.51748
• Mol File: 1357470-29-1.mol

Chemical Properties

• Boiling Point: 642.7±65.0 °C(Predicted)
• Appearance: /
• Density: 1.35±0.1 g/cm3(Predicted)
• Solubility: ≥21.5 mg/mL in DMSO with gentle warming; insoluble in EtOH; insoluble in H2O
• PKA: 7.88±0.42(Predicted)
• CAS DataBase Reference: ON123300(CAS DataBase Reference)
• NIST Chemistry Reference: ON123300(1357470-29-1)
• EPA Substance Registry System: ON123300(1357470-29-1)

Safety Data

• Hazardous Substances Data: 1357470-29-1(Hazardous Substances Data)

Usage

Uses

Used in Brain Tumor Chemotherapy:
ON123300 is used as a potent multikinase inhibitor for brain tumor chemotherapy. Its ability to strongly inhibit Ark5 and CDK4, as well as growth factor receptor tyrosine kinases, makes it a potential candidate for the development of new cancer treatments.
Used in Pharmaceutical Industry:
ON123300 is used as a research compound in the pharmaceutical industry for the development of new cancer therapies. Its multikinase inhibitory properties and potential in brain tumor chemotherapy make it a valuable asset in the search for more effective cancer treatments.

Biological Activity

on123300 is a multi-targeted kinase inhibitor.the signaling hyperactivation of rtk is most commonly caused by egfr mutation/amplification or pdgfr amplification/overexpression. fgfr1signaling also occurs in gbm exhibiting fgfr1 kinase domain gain-of-function mutations.

in vitro

in previous study, when z138c and granta 519 cells were treated with on123300, it was found that on123300 was efficient to inhibit the phosphorylation of rb family proteins. moreover, on123300 was able to inhibit the phosphorylation of proteins that were involved in the pi3k/akt pathway. in addition, on123300-treated cells similarly arrested at lower concentrations, however, higher concentrations could lead to the apoptosis induction [1].

in vivo

previous animal in vivo study showed that mouse xenograft had a strong inhibition of mcl tumor growth in on123300-treated animals. moreover, the treatment with on123300 to ibrutinib-sensitive and -resistant patient-derived mcls was able to trigger apoptosis and inhibition of both rb and pi3k/akt pathways, indicating that on123300 could be an effective drug in the treatment of mcl, such as ibrutinib-resistant forms of the disease [1].

IC 50

3.9, 5, 26, 26, 9.2 and 11 nm for cdk4, ark5, pdgfrβ, fgfr1, ret, and fyn, respectively.

references

[1] divakar sk et al. dual inhibition of cdk4/rb and pi3k/akt/mtor pathways by on123300 induces synthetic lethality in mantle cell lymphomas. leukemia. 2016 jan;30(1):86-93.

Upstream product

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• 109-01-3 1-methyl-piperazine 
• 588-36-3 (4-amino-2-(methylthio)pyrimidin-5-yl)methanol 
• 770-31-0 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde 
• 1537216-36-6 2-methylsulfanyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile 
• 211245-63-5 [4-cyclopentylamino-2-(methylsulfanyl)pyrimidine-5-yl]methanol 
• 211245-64-6 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde 
• 211245-62-4 4-cyclopentylamino-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester 
• 16153-81-4 4-(4-Methyl-piperazino)-anilin 
• 1003-03-8 Cyclopentamine 

Relevant articles and documents

Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5)

The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6- carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.

2-SUBSTITUTED-8-ALKYL-7-OXO-7,8-DIHYDROPYRIDO[2,3-D] PYRIMIDINE-6-CARBONITRILES AND USES THEREOF

Compounds according to Formula (I), as well as salts thereof: wherein R1 and R2 are as defined herein, are useful as antiproliferative agents and kinase inhibitors. Synthetic methods for preparing the compounds of Formula (I) are als