1. Product Overview
MK-8353 (also known as SCH772984 analog / ultra-selective ERK inhibitor, CAS No. 1799328-86-1) is a potent, ATP-competitive, and highly selective small-molecule inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2). With IC50 values of 2 nM for ERK2 and 5 nM for ERK1 in biochemical assays, MK-8353 blocks both the catalytic activity and the phosphorylation of downstream substrates while sparing upstream MEK and RAF kinases. Unlike earlier ERK inhibitors, it maintains strong cellular activity even in the presence of activated BRAF or KRAS mutations. Originally developed by Merck/Schöring-Plough and evaluated in Phase I/II clinical trials for advanced solid tumors, MK-8353 serves as a key pharmacological tool for dissecting MAPK pathway feedback loops, overcoming adaptive resistance to BRAF/MEK inhibitors, and studying ERK-dependent transcription and proliferation in cancer models.
2. Key Features and Advantages
• Ultra-Selective ERK1/2 Blockade: IC50 = 2 nM (ERK2), 5 nM (ERK1); >1,000-fold selectivity over 300+ kinases including MEK1/2, BRAF, p38, JNK, and CDK family members.
• Blocks Both Catalysis and Phosphorylation: Inhibits ERK autophosphorylation and substrate phosphorylation (e.g., RSK) without affecting upstream MEK/RAF signaling, making it ideal for isolating ERK-specific effects.
• Active in KRAS/BRAF-Mutant Models: Potently suppresses pERK and proliferation in BRAF V600E, NRAS, and KRAS G12C/D mutant cell lines and patient-derived xenografts where MEK inhibitors often fail due to feedback reactivation.
• Favorable Drug-Like Profile: MW 412.44, cLogP ~2.8, oral bioavailability in preclinical species, suitable for both in vitro and in vivo MAPK studies.
• Research-Grade Quality: ≥98% purity (HPLC), white to off-white solid, stable as powder at -20°C for years.
3. Main Applications
• MAPK Pathway Dissection: Isolating ERK1/2-specific contributions from MEK/RAF in RAS-RAF-MEK-ERK signaling; monitoring pERK, pRSK, and downstream cyclin D1/c-Myc suppression.
• KRAS/BRAF/NRAS Cancer Research: Overcoming adaptive resistance to BRAF (vemurafenib/dabrafenib) and MEK inhibitors (trametinib) in melanoma, NSCLC, CRC, and pancreatic cancer models.
• Clinical-Stage Reference Compound: MK-8353 was evaluated in Phase I/II trials (NCT02501754) for advanced solid tumors; serves as benchmark ERK inhibitor for newer clinical entrants (ulixertinib/BVD-523, LY3214996).
• Drug Combination Studies: Synergizes with KRAS G12C inhibitors (MRTX1133, adagrasib), SOS1 inhibitors (MRTX0902), or PI3K/AKT blockers to block parallel survival pathways.
• Mechanistic ERK Biology: Studying nuclear translocation of ERK, ELK1 phosphorylation, and ERK-dependent transcription in fibroblasts, neurons, and immune cells.
4. Technical Specifications
5. Storage and Handling
Store powder at -20°C in a tightly sealed, desiccated container protected from light; stable for 2–3 years. Prepare DMSO stock at 10–25 mg/mL (sonicate + warm to 37 °C if needed); aliquot to avoid freeze-thaw and store at -80°C up to 6 months or -20°C up to 1 month. For in vivo, formulate in 10% DMSO with 90% saline, or 5% DMSO/PEG400/Tween80 vehicle; sonicate to clarity at 1–5 mg/mL. Allow vial to reach room temperature before opening; weigh in fume hood with nitrile gloves and goggles.
6. Safety Overview
For laboratory research use only, not for human/veterinary therapeutic or diagnostic use. GHS07 hazard possible (H302 harmful if swallowed, H315/H319 skin/eye irritant). Handle as bioactive kinase inhibitor; wear nitrile gloves, goggles, lab coat; avoid dust inhalation and contact. Dispose as organic chemical waste per local regulations. Include DMSO/saline vehicle controls in all assays.
