Selumetinib

Selumetinib

File:Selumetinib skeletal.svg
Systematic (IUPAC) name
6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide
Clinical data
Legal status	Investigational
Identifiers
CAS Number	606143-52-6
ATC code	None
PubChem	CID: 10127622
IUPHAR/BPS	5665
ChemSpider	8303141 Y
UNII	6UH91I579U
KEGG	D09666 Y
ChEBI	CHEBI:90227
ChEMBL	CHEMBL1614701 Y
Synonyms	AZD6244, ARRY-142886
Chemical data
Formula	C17H15BrClFN4O3
Molecular mass	457.68 g/mol
SMILES CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)Cl)C(=O)NOCCO
InChI InChI=1S/C17H15BrClFN4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26) Y Key:CYOHGALHFOKKQC-UHFFFAOYSA-N Y
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Selumetinib (AZD6244) is a drug that was discovered by Array Biopharma and was licensed to AstraZeneca. It is being investigated for the treatment of various types of cancer, such as non-small cell lung cancer (NSCLC).

Mechanism of action

The gene BRAF is part of the MAPK/ERK pathway, a chain of proteins in cells that communicates input from growth factors. Activating mutations in the BRAF gene, primarily V600E (meaning that the amino acid valine in position 600 is replaced by glutamic acid), are associated with lower survival rates in patients with papillary thyroid cancer. Another type of mutation that leads to undue activation of this pathway occurs in the gene KRAS and is found in NSCLC. A possibility of reducing the activity of the MAPK/ERK pathway is to block the enzyme MAPK kinase (MEK), immediately downstream of BRAF, with the drug selumetinib. More specifically, selumetinib blocks the subtypes MEK1 and MEK2 of this enzyme.

Possible uses

In addition to thyroid cancer, BRAF-activating mutations are prevalent in melanoma (up to 59%), colorectal cancer (5–22%), serous ovarian cancer (up to 30%), and several other tumor types.

Selumetinib has also been shown to inhibit growth of GNAQ mutated uveal melanoma cell lines. Furthermore, preliminary results suggest that selumetinib treatment of uveal melanoma patients can result in tumor shrinkage as the consequence of sustained inhibition of ERK phosphorylation.

KRAS mutations appear in 20 to 30% of NSCLC cases and about 40% of colorectal cancer.

A Phase II clinical trial about selumetinib in NSCLC has been completed in September 2011; one about cancers with BRAF mutations is ongoing as of June 2012.

In July 2015 selumetinib failed a Phase III trial testing whether the drug significantly prolonged the survival of patients in a study on melanoma that has spread to the eye. In the 152-patient trial, a combination of selumetinib and dacarbazine failed to improve progression-free survival compared with just the old drug alone.

As of March 2016 there are other phase 3 trials registered for thyroid cancer, and KRAS Positive NSCLC.