871700-17-3 Usage
Uses
Used in Oncology:
N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide is used as an EGFR kinase inhibitor for the systematic treatment of advanced cutaneous melanoma. Its molecular design allows it to target and inhibit the epidermal growth factor receptor, which is often implicated in the progression of melanoma.
Used in Combination Therapy:
In the pharmaceutical industry, this compound is also used in combination with other targeted therapies, such as BRAF inhibitors like dabrafenib, to treat metastatic melanoma with BRAF V600 mutations. The dual inhibition approach aims to enhance the therapeutic response and overcome potential resistance mechanisms.
Used in Drug Development:
N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide serves as a lead compound in drug development programs focused on discovering new treatments for melanoma and potentially other cancers. Its unique structure and activity profile make it a valuable candidate for further research and optimization.
Used in Research:
In the field of cancer research, this compound is utilized as a tool to study the molecular mechanisms underlying melanoma progression and to identify potential therapeutic targets. Its ability to inhibit EGFR kinase activity makes it a valuable probe for investigating the role of this receptor in cancer biology.
Used in Medicinal Chemistry:
N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide is employed in medicinal chemistry to explore structure-activity relationships and optimize the potency, selectivity, and pharmacokinetic properties of EGFR kinase inhibitors. This research can lead to the development of more effective and safer drugs for cancer treatment.
Biological activity
Trametinib (GSK1120212) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2.
In vitro
For the different subtypes of Raf and MEK, with IC50 ranging from 0.92 nM to 3.4 nM，GSK1120212 inhibits the phosphorylation of MBP. GSK1120212 demonstrates no inhibition of the kinase activities of c-Raf, B-Raf, ERK1 and ERK2. In addition, GSK1120212 does not show drastic inhibitory activity against the other 98 kinases. GSK1120212 displays potent inhibitory activity against human colorectal cancer cell lines. HT-29 and COLO205 cells, which are known to have a constitutively active B-Raf mutant, are most sensitive to GSK1120212 with IC50 0.48 nM and 0.52 nM, respectively. The cell lines bearing a K-Ras mutation show a wide range of sensitivity to GSK1120212 with IC50 of 2.2-174 nM. In contrast, COLO320 DM cells, bearing the wild-type gene in both B-Raf and K-Ras, are found to be resistant to GSK1120212 even at 10 μM. GSK1120212 treatment for 24 hours induces cell-cycle arrest at the G1 phase in all sensitive cell lines. Consistently, GSK1120212 treatment leads to upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines. GSK1120212 induces apoptosis both in HT-29 and COLO205 cells, but that COLO205 cells are more sensitive to GSK1120212 than HT-29 cells in terms of apoptosis induction.GSK1120212 blocks tumor necrosis factor-α and interleukin-6 production from peripheral blood mononuclear cells (PBMCs).
In vivo
Oral administration of GSK1120212 at 0.3 mg/kg or 1 mg/kg once daily for 14 days is effective in inhibiting the HT-29 xenograft growth, and 1 mg/kg of GSK1120212 can completely block the tumor increase. The phosphorylation of ERK1/2 is completely inhibited in the established tumor tissues by single oral dose of 1 mg/kg GSK1120212, and both p15INK4b and p27KIP1 protein levels are upregulated after 14 days of treatment with GSK1120212. In the COLO205 xenograft model, tumor regression is observed even at a dose of 0.3 mg/kg. At a dose of 1 mg/kg, a complete regression is obtained in 4 out of 6 mice in which the tumor degenerates to the point that tumor volume is not measurable. Administration of GSK1120212 at 0.1 mg/kg almost completely suppresses adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) in Lewis rats or DBA1/J mice, respectively.
Features
More potent than PD0325901 or AZD6244.
References
https://en.wikipedia.org/wiki/Trametinib
https://www.novartisoncology.com/news/product-portfolio/mekinist
References
1) Gilmartin?et al.?(2011),?GSK1120212 (JTP-74057) is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition; Clin. Cancer Res.?17?989
2) Abe?et al. (2011),?Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO solvate); ACS Med. Chem. Lett.?2?320
3) Allegrezza?et al.?(2016),?Trametinib Drives T-cell-Dependent Control of KRAS Tumors by Inhibiting Pathological Myelopoiesis; Cancer Res.?76?6253
4) Vella?et al.?(2014),?MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells; Cancer Immunol. Res.?2?351
5) Yamaguchi?et al.?(2012),?Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide; Inflamm. Res.?61?445
Indications
MEK, also known as MAPK, is a dual specificity threonine/tyrosine kinase that is a key node in the Raf–Ras–MEK signaling pathway. Small-molecule MEK inhibitors represent the largest group of type III allosteric inhibitors that do not bind to the ATP binding pocket. As of December 2016, besides the FDA-approved MEK1/2 inhibitors trametinib (Mekinist(R), GlaxoSmithKline) and cobimetinib (Cotellic(R), Roche), over 10 MEK inhibitors are currently in clinical trials. Trametinib was approved by FDA in 2013 for the treatment of patients with either B-Raf V600E or V600K mutated metastatic melanoma. Considering the fact that MEK and Raf are different kinases along the same pathway of Ras–Raf–MEK/ERK signaling cascade, combination strategies using both MEK and B-Raf inhibitors were utilized to overcome the observed progression using single-agent trametinib, which usually occurs within 7months. FDA approved the combination of trametinib and dabrafenib for the treatment of B-Raf V600E/K mutated metastatic melanoma in January 2014 and the combination of cobimetinib and vemurafenib for the same type of indication. Although significant improvement in progression-free survival was observed using MEK/B-Raf combination strategy, the incidence of some common adverse effects, such as vomiting, diarrhea, nausea, rash, and pyrexia, also increased.
Clinical Use
Trametinib (GSK1120212) is an oral MEK inhibitor which has demonstrated
excellent results in combination therapy for BRAF-mutated melanoma and is FDA
approved in combination with BRAF inhibitors for that indication. Trametinib was
evaluated initially as a single agent in KRAS mutant NSCLC in comparison with
docetaxel and pemetrexed. Results as a single agent were not impressive, with an
ORR of only 12% in these patients.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine - increased risk
of agranulocytosis.
Metabolism
Metabolised mainly by deacetylation alone or in
combination with mono-oxygenation. The deacetylated
metabolite was further metabolised by glucuronidation.
CYP3A4 oxidation is considered a minor pathway
of metabolism. The deacetylation is mediated by
the carboxyl-esterases 1b, 1c and 2, with possible
contributions by other hydrolytic enzymes.
Total dose recovery was low after a 10-day collection
period (<50%) following administration of a single
oral dose of radiolabelled trametinib, due to the long
elimination Half-life. Trametinib was excreted mainly
in the faeces (>80% of recovered radioactivity) and to a
minor extent in urine (≤19%).
Check Digit Verification of cas no
The CAS Registry Mumber 871700-17-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,7,1,7,0 and 0 respectively; the second part has 2 digits, 1 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 871700-17:
(8*8)+(7*7)+(6*1)+(5*7)+(4*0)+(3*0)+(2*1)+(1*7)=163
163 % 10 = 3
So 871700-17-3 is a valid CAS Registry Number.
871700-17-3Relevant articles and documents
Method for synthesizing key intermediate of trametinib
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Paragraph 0029, (2019/02/27)
The invention discloses a method for synthesizing a key intermediate of trametinib, malonic acid monomethyl amide monoethyl ester and isosuccinic acid have a ring-closure reaction to obtain a crude product of a pyridine triketone compound; the obtained cr
Method for synthesizing trametinib
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, (2019/02/25)
The invention discloses a method for synthesizing trametinib. The method comprises the steps of dehydrating N-(2-fluoro-4-iodophenyl)-N'-methylurea to form carbodiimide, then enabling the product to be subjected to a cyclization reaction with 2-methyl-3-o
SOLVATE FORM M OF TRAMETINIB DIMETHYL SULFOXIDE AND METHODS OF MAKING AND USING THEREOF
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Paragraph 0093, (2015/06/10)
The present invention relates to a crystalline Form M of trametinib dimethyl sulfoxide solvate. Comparing with the prior art, Form M is a more stable crystalline form with better particle size distribution and good flowability and is non-hygroscopic. Ther
5-AMINO-2,4,7-TRIOXO-3,4,7,8-TETRAHYDRO-2H-PYRIDO’2,3-D! PYRIMIDINE DERIVATIVES AND RELATED COMPOUNDS FOR THE TREATMENT OF CANCER
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Page/Page column 149, (2008/06/13)
The present invention relates to a pyrimidine compound represented by the following formula [I] wherein each symbol is as defined in the specification, a pharmaceutically acceptable salt thereof, and a pharmaceutical agent for the prophylaxis or treatment of a disease caused by undesirable cell proliferation, particularly an antitumor agent, which contains such compound. The compound of the present invention has superior undesirable cell proliferation suppressing action, particularly, an antitumor action, and is useful as an antitumor agent for the prophylaxis or treatment of cancer, antirheumatoid agent and the like. In addition, by the combined use with other antitumor agent such as alkylating agent, metabolism antagonist and the like, it can be a more effective antitumor agent.
