| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| Other Sizes |
| Targets |
Bcr-Abl:5 nM (IC50, p210Bcr-Abl kinase); Src:0.8 nM (IC50); KIT:50 nM (IC50)
PD180970 primarily targets the Bcr-Abl fusion protein, a constitutively active tyrosine kinase that drives the proliferation of leukemic cells in CML. It is an ATP-competitive inhibitor, meaning it competes with ATP for binding to the kinase domain of Bcr-Abl. In addition to Bcr-Abl, PD180970 also inhibits Src kinase (IC50 = 0.8 nM) and KIT kinase (IC50 = 50 nM). This multi-kinase inhibitory profile suggests it may have broader applications in targeting other malignancies driven by these kinases. |
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| ln Vitro |
K562 cells are killed by PD180970 (0.5 μM; 24-96 hours) treatment[1]. Treatment with PD180970 (0.5 μM; 24-48 hours) causes K562 cells to undergo apoptosis. An increase in annexin V-PI double-positive cells is shown by the results [1]. PD180970 suppresses the kinase activity of pure recombinant Abl tyrosine kinase (IC50 of 2.2 nM) as well as the tyrosine phosphorylation of p210Bcr-Abl, Gab2, and CrkL in K562 cells (405 nM, 80 nM, and 80 nM, respectively). With an IC50 of 5 nM, the human K562 CML cell line's Bcr-Abl kinase activity was blocked using PD180970, which inhibited Stat5 DNA-binding activity[2].
PD180970 demonstrates potent in vitro activity against Bcr-Abl-positive cells. It inhibits the autophosphorylation of p210 Bcr-Abl with an IC50 of 5 nM. Furthermore, it inhibits the tyrosine phosphorylation of downstream signaling molecules in the Bcr-Abl pathway, such as Grb2-associated binder 2 (Gab2) and Crk-like protein (CrkL), with IC50 values of 170 nM and 80 nM, respectively. PD180970 also effectively inhibits the proliferation of K562 cells, with an IC50 of 0.5 μM. The compound shows high potency against both wild-type and mutant forms of Bcr-Abl. |
| ln Vivo |
In mice, PD180970 (5 mg/kg; intraperitoneal injection; daily; for 7 days) reduces the loss of neurons caused by MPTP. According to a preclinical animal model of Parkinson's disease (PD), PD180970 possesses neuroprotective properties [4].
In vivo studies have demonstrated the therapeutic potential of PD180970 in animal models of CML. It has shown efficacy in inhibiting tumor growth in xenograft models, confirming its ability to suppress Bcr-Abl-driven malignancies. While detailed in vivo data is limited, its potency and mechanism of action support its development as a novel therapeutic agent for Bcr-Abl-positive leukemia. The compound has also been shown to induce apoptosis in K562 leukemic cells, further supporting its anti-leukemic activity. |
| Enzyme Assay |
The primary in vitro assay for PD180970 is a kinase activity assay using purified recombinant Bcr-Abl enzyme. The enzyme is incubated with a peptide substrate and ATP in the presence of varying concentrations of the compound. The extent of phosphorylation is measured, typically using radiolabeled ATP or a fluorescent readout, to determine the IC50 value of 5 nM for autophosphorylation inhibition. Similar assays are used to profile its activity against other kinases like Src and KIT.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: K562 cells Tested Concentrations: 0.5 μM Incubation Duration: 24 hrs (hours), 48 hrs (hours), 72 hrs (hours), 96 hrs (hours) Experimental Results: Resulted in cell death. Apoptosis Analysis[1] Cell Types: K562 cells Tested Concentrations: 0.5 μM Incubation Duration: 24 hrs (hours), 48 hrs (hours) Experimental Results: Increased annexin V-positive/PI-negative cells. Cellular assays for PD180970 involve treating Bcr-Abl-positive cell lines, such as K562, with the compound. The inhibition of Bcr-Abl autophosphorylation and downstream signaling is assessed by Western blotting using phospho-specific antibodies. Cell proliferation and viability are measured using standard assays like MTT or CellTiter-Glo over 24-96 hours. Apoptosis induction is quantified by flow cytometry using Annexin V and propidium iodide (PI) staining. |
| Animal Protocol |
Animal/Disease Models: Male C57BL /6J mice (3-4 months old) injected with MPTP[4]
Doses: 5 mg/kg Route of Administration: Intraperitonial injection; daily; for 7 days Experimental Results: diminished number of activated microglia on activation by MPTP in mice brains. And demonstrated significant reduction in intensity of Iba1 expression in activated microglia. In vivo efficacy of PD180970 is typically evaluated in mouse xenograft models using Bcr-Abl-positive tumor cell lines. Tumor-bearing mice are treated with the compound, and tumor growth inhibition is monitored. The compound can be formulated for oral or intraperitoneal administration. Pharmacodynamic markers, such as the inhibition of Bcr-Abl phosphorylation in tumor tissue, are also assessed to confirm target engagement. |
| ADME/Pharmacokinetics |
PD180970 has a molecular weight of 429.27 g/mol and a molecular formula of C21H15Cl2FN4O. It is soluble in DMSO at 100 mg/mL. For in vivo studies, it can be formulated in a vehicle such as 10% DMSO in corn oil. The compound is stable as a powder at -20°C for up to three years. Detailed pharmacokinetic parameters, such as half-life and bioavailability, are not widely available in public literature.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for PD180970 is limited, as it is primarily a research compound. However, its high potency against kinases suggests potential for on-target toxicities. As a kinase inhibitor, it may have effects on normal cellular processes that rely on the inhibited kinases. Standard safety precautions should be observed when handling this compound in a laboratory setting.
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| References |
[1]. J F Dorsey, et al. The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. Cancer Res. 2000 Jun 15;60(12):3127-31.
[2]. Mei Huang, et al. Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. Oncogene. 2002 Dec 12;21(57):8804-16. [3]. Amie S Corbin, et al. Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood. 2004 Dec 1;104(12):3754-7. [4]. Suresh Sn, et al. Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration. EBioMedicine. 2019 Dec;50:260-273. |
| Additional Infomation |
PD180970 is a research-grade compound developed for investigating Bcr-Abl-driven cancers, particularly CML. Its ability to inhibit both wild-type and mutant Bcr-Abl makes it a promising candidate for overcoming imatinib resistance. While it has not progressed to clinical trials, it serves as a valuable tool compound for studying the Bcr-Abl signaling pathway and for the development of next-generation Bcr-Abl inhibitors.
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| Molecular Formula |
C21H15CL2FN4O
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|---|---|
| Molecular Weight |
429.27
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| Exact Mass |
428.061
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| CAS # |
287204-45-9
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| PubChem CID |
5311104
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.915
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
29
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| Complexity |
640
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SLCFEJAMCRLYRG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H15Cl2FN4O/c1-11-8-13(6-7-17(11)24)26-21-25-10-12-9-14(20(29)28(2)19(12)27-21)18-15(22)4-3-5-16(18)23/h3-10H,1-2H3,(H,25,26,27)
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| Chemical Name |
6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylanilino)-8-methylpyrido[2,3-d]pyrimidin-7-one
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| Synonyms |
PD180970 PD180970 PD180970
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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 |
| 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) |
DMSO : ~100 mg/mL (~232.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3295 mL | 11.6477 mL | 23.2954 mL | |
| 5 mM | 0.4659 mL | 2.3295 mL | 4.6591 mL | |
| 10 mM | 0.2330 mL | 1.1648 mL | 2.3295 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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