| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
MEK1/2
MEK1, MEK2 (as a ligand component in PROTAC design) |
|---|---|
| ln Vitro |
PD0325901, a non-ATP competitive MEK inhibitor, effectively suppresses tumor cell growth and ERK signaling[1].
MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) are the "gatekeepers" of the ERK signaling output with redundant roles in controlling ERK activity. Numerous inhibitors targeting MEK1/2 have been developed including three FDA-approved drugs. However, acquired resistance to MEK1/2 inhibitors has been observed in patients, and new therapeutic strategies are needed to overcome the resistance. Here, we report a first-in-class degrader of MEK1/2, MS432 (23), which potently and selectively degraded MEK1 and MEK2 in a VHL E3 ligase- and proteasome-dependent manner and suppressed ERK phosphorylation in cells. It inhibited colorectal cancer and melanoma cell proliferation much more effectively than its negative control MS432N (24), and its effect was phenocopied by MEK1/2 knockdown. Compound 23 was highly selective for MEK1/2 in global proteomic profiling studies. It was also bioavailable in mice and can be used for in vivo efficacy studies. We provide two well-characterized chemical tools to the biomedical community.[1] PD0325901, the parent compound, is a non‑ATP competitive MEK inhibitor that potently inhibits ERK signaling and suppresses tumor cell proliferation. PD0325901-O-C2-dioxolane retains the MEK‑binding properties of PD0325901, enabling its use as a target protein ligand in PROTACs. When incorporated into a PROTAC, it facilitates MEK1/2 binding and subsequent degradation via the ubiquitin‑proteasome pathway. |
| ln Vivo |
As a PROTAC ligand intermediate, PD0325901-O-C2-dioxolane itself is not designed for direct in vivo activity. However, when conjugated to an E3 ligase ligand and linker, the resulting PROTAC degrader can achieve potent MEK1/2 degradation in cells. For example, related MEK PROTACs have demonstrated DC₅0 values in the nanomolar range and in vivo efficacy in mouse models.
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| Enzyme Assay |
PD0325901-O-C2-dioxolane is not directly used in non‑cellular binding assays. Instead, it serves as a synthetic building block. For quality control, the compound is characterized by NMR and LC‑MS for identity and purity (>97%). It is typically stored at ‑20degC as a solid and dissolved in DMSO (up to 100 mg/mL) for use in PROTAC synthesis or biological evaluation.
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| Cell Assay |
PD0325901-O-C2-dioxolane is typically dissolved in DMSO to prepare stock solutions and further diluted in cell culture media (final DMSO ≤0.1%) for cellular studies. It is often used in PROTAC synthesis, and cellular activity is assessed for the final PROTAC molecule rather than the intermediate itself.
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| Animal Protocol |
As a PROTAC ligand intermediate, PD0325901-O-C2-dioxolane is typically used in ex vivo or in vivo settings only after being fully conjugated into a PROTAC molecule. The final PROTAC degrader is evaluated in mouse xenograft models or PK studies. Direct in vivo experiments using the intermediate itself have not been reported.
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| ADME/Pharmacokinetics |
PK data for PD0325901-O-C2-dioxolane itself has not been reported, as it is an intermediate used in PROTAC synthesis rather than a drug candidate. However, its parent compound PD0325901 is known to be orally bioavailable with moderate plasma half‑life. PD0325901-O-C2-dioxolane is likely to be metabolized in vivo.
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| Toxicity/Toxicokinetics |
No toxicity data for PD0325901-O-C2-dioxolane has been reported. As a structural analog of PD0325901, it may share class‑related toxicity profiles of MEK inhibitors when used systemically. However, as a PROTAC intermediate, its toxicological profile is typically evaluated only in the context of the final degrader molecule.
|
| References | |
| Additional Infomation |
MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) are the "gatekeepers" of the ERK signaling pathway output, playing a redundant role in controlling ERK activity. Several inhibitors targeting MEK1/2 have been developed, including three FDA-approved drugs. However, acquired resistance to MEK1/2 inhibitors has been observed in patients, necessitating novel therapeutic strategies to overcome this resistance. This article reports a first-in-class MEK1/2 degrader, MS432 (23), which efficiently and selectively degrades MEK1 and MEK2 in a VHL E3 ligase- and proteasome-dependent manner, and inhibits ERK phosphorylation in cells. Compared to the negative control MS432N (24), MS432 more effectively inhibited the proliferation of colorectal cancer and melanoma cells, and MEK1/2 knockdown mimicked its inhibitory effect. Compound 23 exhibited high selectivity for MEK1/2 in a full proteomics analysis. It also has bioavailability in mice and can be used for in vivo efficacy studies. We have provided the biomedical community with two well-defined chemical tools. [1]
PD0325901-O-C2-dioxolane (CAS: 2581116-22-3; formula: C1₈H1₆F3IN2O4; MW: 508.23) contains a dioxolane protecting group and serves as a versatile synthetic handle for linker conjugation. Its solubility in DMSO is 80‑100 mg/mL, with a solid form stable at ‑20degC. This compound is intended for research use only and is not approved for clinical applications. |
| Molecular Formula |
C18H16F3IN2O4
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|---|---|
| Molecular Weight |
508.23
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| Exact Mass |
508.010
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| CAS # |
2581116-22-3
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| Related CAS # |
MS432;2672512-44-4
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| PubChem CID |
154573762
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| Appearance |
White to off-white solid powder
|
| LogP |
4.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
28
|
| Complexity |
515
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C(NOCCC1OCCO1)(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F
|
| InChi Key |
OGHJINAFAYYQDK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C18H16F3IN2O4/c19-12-3-2-11(18(25)24-28-6-5-15-26-7-8-27-15)17(16(12)21)23-14-4-1-10(22)9-13(14)20/h1-4,9,15,23H,5-8H2,(H,24,25)
|
| Chemical Name |
N-[2-(1,3-dioxolan-2-yl)ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide
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| Synonyms |
PD0325901-O-C2-dioxolane; 2581116-22-3; PD0325901-O-C2-dioxolane; 2581116-22-3; N-[2-(1,3-dioxolan-2-yl)ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide; SCHEMBL24072690;
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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 (196.76 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.92 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 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 (4.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9676 mL | 9.8381 mL | 19.6761 mL | |
| 5 mM | 0.3935 mL | 1.9676 mL | 3.9352 mL | |
| 10 mM | 0.1968 mL | 0.9838 mL | 1.9676 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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