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| Targets |
MEK1 and MEK2 (MAPK/ERK kinases). PD184161 is a potent, non-ATP-competitive inhibitor of MEK1 and MEK2. MEK1 and MEK2 are dual-specificity kinases that phosphorylate and activate ERK1 and ERK2, which are downstream effectors of the RAS-RAF-MEK-ERK signaling cascade. This pathway is frequently hyperactivated in cancer and is a major driver of cell proliferation, survival, and migration. PD184161 inhibits MEK activity with an IC50 of 10-100 nM in a time- and concentration-dependent manner. The compound's non-ATP-competitive mechanism of action distinguishes it from ATP-competitive kinase inhibitors and may contribute to its selectivity and prolonged target engagement. PD184161 inhibits cell proliferation and induces apoptosis. The compound has been shown to significantly suppress tumor engraftment and initial growth in tumor xenografts. However, PD184161 is unable to suppress MEK activity in HCC xenografts in the long term, suggesting potential resistance mechanisms. PD184161 also produces depressive-like behavior, indicating effects on the central nervous system.
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| ln Vitro |
Inducing apoptosis and inhibiting cell proliferation, PD184161 (1–20 μM) exhibits concentration- and time-dependent effects [1]. A one-hour dose of 0.1 and 1.0 μM PD184161,2 inhibits phosphorylation of ERK1,2 [1]. PD184161 (5 μM; 30 min) protects against the toxic effects of bicuculline [3].
PD184161 demonstrates potent inhibition of MEK activity with an IC50 of 10-100 nM. The compound is a time- and concentration-dependent inhibitor of MEK. PD184161 inhibits cell proliferation in hepatocellular carcinoma (HCC) cells and other cancer cell lines. The compound induces apoptosis at concentrations of ≥1.0 μM. PD184161 significantly suppresses tumor engraftment and initial growth in tumor xenografts. However, the compound is unable to suppress MEK activity in HCC xenografts in the long term, indicating potential resistance mechanisms. PD184161 also produces depressive-like behavior in animal models, indicating central nervous system effects that may be relevant for understanding the compound's pharmacology and potential side effects. PD184161's potent MEK inhibition and anti-proliferative activity make it a valuable tool for studying the MAPK/ERK pathway and validating MEK as a therapeutic target. |
| ln Vivo |
After oral administration, PD184161 decreases P-ERK levels in tumor xenografts in 3–12 hours [1]. PD184161, administered orally twice daily for 38 days at a dose of 300 mg/kg, dramatically slowed the growth and implantation of tumors [1]. A single injection of PD184161, at a dose of 30 mg/kg, induces depressive-like symptoms [2]. After a stroke, PD184161, administered intravenously at a dose of 500 μg/kg, stops the progression of neurological impairments and brain damage [3].
PD184161 is an orally active MEK inhibitor. The compound significantly suppresses tumor engraftment and initial growth in tumor xenografts. However, PD184161 is unable to suppress MEK activity in HCC xenografts in the long term, suggesting that resistance mechanisms may limit its long-term efficacy. PD184161 produces depressive-like behavior in animal models, indicating that the compound has central nervous system effects. The compound's oral activity and potent MEK inhibition make it a valuable tool for studying the MAPK/ERK pathway in vivo. PD184161 has been used in research to explore the role of MEK in cancer and other diseases. Detailed pharmacokinetic and pharmacodynamic data are limited in publicly available sources, but the compound's in vivo activity has been demonstrated in preclinical models. |
| Enzyme Assay |
MEK kinase activity assays are performed using recombinant MEK1 or MEK2 enzyme and a substrate (e.g., inactive ERK1/2 or a peptide substrate). The enzyme is incubated with the substrate and [γ-³²P]ATP in kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM DTT). The reaction is incubated at 30°C for 30-60 minutes. Phosphorylated substrate is quantified by scintillation counting or by Western blotting using phospho-specific antibodies (e.g., anti-phospho-ERK). PD184161 is serially diluted in DMSO and added to the reaction mixture. The IC50 for PD184161 is 10-100 nM. Each concentration is tested in duplicate, and IC50 values are calculated by non-linear regression analysis. Appropriate positive controls (e.g., known MEK inhibitors like PD184352 or trametinib) and vehicle controls are included to validate the assay.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: HCC cell lines (HepG2, Hep3B, PLC and SKHep) Tested Concentrations: 1-20 μM Incubation Duration: 24, 48 or 72 hrs (hours) Experimental Results: Cell proliferation was inhibited. Apoptosis analysis[1] Cell Types: HCC cell lines (HepG2, Hep3B, PLC and SKHep) Tested Concentrations: 1-20 μM Incubation Duration: 48 hrs (hours) Experimental Results: Induction of apoptosis. Western Blot Analysis[1] Cell Types: HCC cell lines (HepG2, Hep3B, PLC and SKHep) Tested Concentrations: 0.1 and 1.0 μM Incubation Duration: 1 hour Experimental Results: ERK1,2 phosphorylation is inhibited. Cell viability assay[3] Cell Types: Primary Mouse Neurons Tested Concentrations: 5 μM Incubation Duration: 30 min Experimental Results: Protection against toxic effects of bicuculline. Cellular MEK inhibition is evaluated in cancer cell lines, including hepatocellular carcinoma (HCC) cells and other cancer types. Cells are cultured in appropriate media (e.g., DMEM with 10% FBS) at 37°C with 5% CO₂ and treated with PD184161 at concentrations ranging from 0.1 to 10 μM for 24-72 hours. MEK activity is assessed by measuring phosphorylation of ERK1/2 (p-ERK) by Western blotting using phospho-specific antibodies. Cell viability and proliferation are assessed using MTT, CCK-8, or CellTiter-Glo assays. Apoptosis is evaluated by Annexin V/PI staining, caspase-3/7 activity assays, and PARP cleavage Western blotting. Cell cycle analysis is performed by propidium iodide staining and flow cytometry. Each experiment includes vehicle controls (DMSO) and appropriate positive controls (e.g., known MEK inhibitors). |
| Animal Protocol |
Animal/Disease Models: Hep3B tumor xenograft BALB/c athymic nude mice [1]
Doses: 300 mg/kg Route of Administration: Orogastric gavage, twice a day for 38 days Experimental Results: diminished early tumor growth. Animal/Disease Models: Male, 6weeks old C57Bl/6 mice [2] Doses: 500 μg/kg Route of Administration: intravenous (iv) (iv)injection 30 minutes before MCAO or PTZ administration Experimental Results: Prevent the progression of neurological deficits and brain damage after stroke. Animal/Disease Models: C57Bl/6 mice [3] Doses: 30 mg/kg Route of Administration: intraperitoneal (ip) injection, single injection Experimental Results:depressive-like behavior. In vivo efficacy of PD184161 is evaluated in mouse xenograft models using cancer cell lines, including hepatocellular carcinoma (HCC) cells. Tumor cells are implanted subcutaneously in immunodeficient mice. When tumors reach a predetermined size, mice are randomized into treatment and control groups. PD184161 is administered orally at doses determined by preclinical studies. The compound is formulated in appropriate vehicles (e.g., DMSO/PEG300/Tween 80 or CMC-Na suspension). Tumor growth is monitored by caliper measurements. Body weight and clinical signs are monitored throughout the study to assess tolerability. At study endpoint, tumors are harvested for histopathological analysis, immunohistochemistry (Ki67 for proliferation, cleaved caspase-3 for apoptosis), and biochemical assays (p-ERK levels, MEK activity). Sample sizes typically range from 6-10 animals per group. PD184161 significantly suppresses tumor engraftment and initial growth but is unable to suppress MEK activity in HCC xenografts in the long term. |
| ADME/Pharmacokinetics |
Molecular Weight: 557.55. Formula: C17H13BrClF2IN2O2. CAS No.: 212631-67-9. Purity: ≥98% (HPLC). Appearance: Crystalline solid. Solubility: DMF: 30 mg/mL; DMSO: ≥10 mg/mL. Storage: Powder at -20°C. PD184161 is a potent, orally active MEK inhibitor with an IC50 of 10-100 nM. PD184161 inhibits cell proliferation and induces apoptosis. PD184161 produces depressive-like behavior. PD184161 significantly suppresses tumor engraftment and initial growth in tumor xenografts but is unable to suppress MEK activity in HCC xenografts in the long term.
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| Toxicity/Toxicokinetics |
No comprehensive toxicology data are publicly available for PD184161. The compound is intended for research use only and has not undergone full preclinical toxicology evaluation required for clinical development. As a MEK inhibitor, potential adverse effects may include skin rash, diarrhea, and other class effects associated with MEK targeting. PD184161 produces depressive-like behavior in animal models, indicating central nervous system effects that may be relevant for understanding the compound's safety profile. Standard toxicity studies would include acute toxicity assessment in rodents, repeated dose toxicity studies (14-day and 28-day), and genotoxicity screening (Ames test, micronucleus assay). PD184161 is for research use only and not for human therapeutic use.
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| References |
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| Additional Infomation |
PD184161 is also known as PD-184161. Its IUPAC name is 5-bromo-2-((2-chloro-4-iodophenyl)amino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide. PD184161 is a potent, orally active MEK inhibitor with an IC50 of 10-100 nM. PD184161 is structurally related to CI-1040 (PD184352). PD184161 inhibits cell proliferation and induces apoptosis. PD184161 produces depressive-like behavior. PD184161 significantly suppresses tumor engraftment and initial growth in tumor xenografts but is unable to suppress MEK activity in HCC xenografts in the long term. No clinical trials have been reported for this compound. PD184161 is for research use only.
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| Molecular Formula |
C17H13BRCLF2IN2O2
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| Molecular Weight |
557.55
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| Exact Mass |
555.886
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| CAS # |
212631-67-9
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| PubChem CID |
9937619
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| Appearance |
Off-white to gray solid powder
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| Density |
1.9±0.1 g/cm3
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| Index of Refraction |
1.670
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| LogP |
9.28
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
505
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VJNZMSLGVUSPCF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H13BrClF2IN2O2/c18-11-6-10(17(25)24-26-7-8-1-2-8)16(15(21)14(11)20)23-13-4-3-9(22)5-12(13)19/h3-6,8,23H,1-2,7H2,(H,24,25)
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| Chemical Name |
5-bromo-2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide
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| Synonyms |
PD184161; PD 184161; PD184161
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 (~179.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.48 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (4.48 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 25.0 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 | 1.7936 mL | 8.9678 mL | 17.9356 mL | |
| 5 mM | 0.3587 mL | 1.7936 mL | 3.5871 mL | |
| 10 mM | 0.1794 mL | 0.8968 mL | 1.7936 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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