|Chemical and physical data|
|Molar mass||457.68 g/mol|
|3D model (Jmol)|
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.
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.
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.
- Troiani, T.; Vecchione, L.; Martinelli, E.; Capasso, A.; Costantino, S.; Ciuffreda, L. P.; Morgillo, F.; Vitagliano, D.; d'Aiuto, E.; De Palma, R.; Tejpar, S.; Van Cutsem, E.; De Lorenzi, M.; Caraglia, M.; Berrino, L.; Ciardiello, F. (2012). "Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase a activation in human lung and colorectal cancer cells". British Journal of Cancer. 106 (10): 1648–1659. doi:10.1038/bjc.2012.129. PMC . PMID 22569000.
- Davies, H.; Bignell, G. R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M. J.; Bottomley, W.; Davis, N.; Dicks, E.; Ewing, R.; Floyd, Y.; Gray, K.; Hall, S.; Hawes, R.; Hughes, J.; Kosmidou, V.; Menzies, A.; Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.; Gusterson, B. A.; Cooper, C.; Shipley, J. (2002). "Mutations of the BRAF gene in human cancer". Nature. 417 (6892): 949–954. doi:10.1038/nature00766. PMID 12068308.
- "Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance". Clinical Cancer Research. 18: 3552–3561. Jul 1, 2012. doi:10.1158/1078-0432.CCR-11-3086.
- "Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma". 2012.
- Clinical trial number NCT00890825 for "Comparison of AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive Non Small Cell Lung Cancer (NSCLC) Patients" at ClinicalTrials.gov
- Clinical trial number NCT00888134 for "AZD6244 in Cancers With BRAF Mutations" at ClinicalTrials.gov
- "AstraZeneca - AstraZeneca provides update on selumetinib in uveal melanoma". astrazeneca.com.
- "AstraZeneca's once-lauded drug flunks a Phase III eye cancer trial". FierceBiotech.
- Study Comparing Complete Remission After Treatment With Selumetinib/Placebo in Patient With Differentiated Thyroid Cancer (ASTRA)
- Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1)
- Ho, Alan L.; Grewal, Ravinder K.; Leboeuf, Rebecca; Sherman, Eric J.; Pfister, David G.; Deandreis, Desiree; Pentlow, Keith S.; Zanzonico, Pat B.; et al. (2013). "Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer". New England Journal of Medicine. 368 (7): 623–32. doi:10.1056/NEJMoa1209288. PMC . PMID 23406027.