Trametinib

Trametinib (GSK1120212) is an orally bioavailable MEK1/2 inhibitor approved for the treatment of melanoma and other cancers driven by the MAPK/ERK pathway. Trametinib inhibits B-RAF- and C-RAF-induced phosphorylation of MEK1 and MEK2 with high potency. As an API, Trametinib is manufactured under strict quality controls to ensure consistent therapeutic efficacy. Trametinib suppresses METTL3 expression and normalizes RCAN1 m6A modification, demonstrating effects beyond MEK inhibition. In pharmaceutical quality control, Trametinib reference standards are used for analytical method development, method validation, and ANDA applications. The dimethyl sulfoxide solvate form (HY-10999A) is more commonly used due to the poor aqueous solubility of Trametinib.

Product Parameters

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Parameter	Specification
Product Name	Trametinib
CAS Number	871700-17-3
Molecular Formula	C₂₆H₂₃FIN₅O₄
Molecular Weight	615.39 g/mol
Melting Point	300–301 °C
Density	1.74
Solubility	Soluble in DMSO (up to 20 mg/mL)
pKa	14.76 ± 0.70 (predicted)
Physical Form	White solid
Storage Condition	–20 °C

Bioactivity

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Trametinib (GSK1120212) is a highly specific and potent MEK1/2 inhibitor with an IC50 of 0.92 nM/1.8 nM, and exhibits no inhibitory activity against c-Raf, B-Raf, or ERK1/2.

 

In Vitro Study

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Trametinib GSK1120212 inhibits the phosphorylation of MBP, with IC50 values ranging from 0.92 nM to 3.4 nM for different Raf and MEK subtypes. GSK1120212 exhibits no inhibitory effect on the kinase activities of c-Raf, B-Raf, ERK1, or ERK2. Additionally, it shows weak inhibitory activity against the other 98 kinases. GSK1120212 demonstrates potent inhibitory effects on human colon cancer cell lines, particularly HT-29 and COLO205 cells, which harbor constitutively active B-Raf mutations; these two cell lines exhibit the highest sensitivity to GSK1120212, with IC50 values of 0.48 nM and 0.52 nM, respectively. Cell lines harboring K-Raf mutations show varying sensitivity to GSK1120212, with IC50 ranges of 2.2–174 nM. In contrast, COLO320DM cells carry both wild-type B-Raf and K-Ras, resulting in resistance to GSK1120212 even at concentrations as high as 10 μM. Treatment with GSK1120212 for 24 hours induces cell cycle arrest in all sensitive cell lines at the G1 phase. Consistent with this, GSK1120212 increases the expression levels of p15INK4b and/or p27KIP1 in most colon cancer cell lines. Furthermore, GSK1120212 induces apoptosis in HT-29 and COLO205 cells, with COLO205 cells demonstrating higher sensitivity. GSK1120212 inhibits the production of tumor necrosis factor-α and interleukin-6 by peripheral blood monocytes.

 

In Vivo Studies

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Oral administration of GSK1120212 at doses of 0.3 mg/kg or 1 mg/kg once daily for 14 days effectively inhibits HT-29 tumors, with the 1 mg/kg dose achieving complete suppression of tumor growth. In cancer tissues, a single oral dose of 1 mg/kg GSK1120212 fully inhibits ERK1/2 phosphorylation and increases the expression levels of p15INK4b and p27KIP1 after 14 days. In the COLO205 tumor model, a 0.3 mg/kg dose of GSK1120212 was sufficient to inhibit tumor growth, while a 1 mg/kg dose reduced tumor size in two-thirds of mice to undetectable levels. A 0.1 mg/kg dose of GSK1120212 completely suppressed adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) in Lewis rats or DBA1/J mice.

 

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