Usage
It is a tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2 currently in clinical development.
Description
Selumetinib (AZD6244; ARRY-142886) is an oral MEK inhibitor. In a randomized trial, NSCLC patients with wild-type KRAS were randomized to erlotinib
alone or combination therapy with selumetinib, while mutant KRAS patients were
randomized to selumetinib alone or combination therapy. The primary end points
were PFS for the KRAS wild-type cohort and objective response rate (ORR) for the
KRAS mutant cohort. Results were not impressive, with no PFS difference in the
KRAS wild-type arm (2.4 vs. 2.1?months) and no ORR difference in the KRASmutated subgroup (0% vs. 10%). A planned trial of selumetinib in combination
with the anti-PD-L1 antibody durvalumab has since been suspended (NCT03004105).
Uses
It is a tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2 currently in clinical development.
Definition
ChEBI: A member of the class of benzimidazoles that is 1-methyl-1H-benzimidazole which is substituted at positions 4, 5, and 6 by fluorine, (4-bromo-2-chlorophenyl)amino, and N-(2-hydroxyethoxy)aminocarbonyl groups, respectiv
ly. It is a MEK1 and MEK2 inhibitor.
General Description
Class: dual threonine/tyrosine kinase;
Treatment: children with NF1; Other name: AZD-6244, ARRY-142886;
Oral bioavailability = 62%;
Elimination half-life = 6.2 h;
Protein binding = 97.7%
Metabolism
Following oral administration of radiolabeled
selumetinib, the most prominent drug-related
component in the plasma was selumetinib,
accounting for 40% of the plasma radioactivity. The
major circulating metabolite was an amide
glucuronide 2, which accounted for 22% of the
plasma radioactivity. This metabolite resulted from loss of the ethanediol moiety to give the primary
amide 1, which underwent glucuronidation and an
additional loss of 2 mass units, most likely due to
further oxidation of the N-methylbenzimidazole
moiety (Fig. 5).
Dosage
Selumetinib is characterized by a moderate oral
bioavailability (62%) and a relatively short half-life
(6.2 h), and these properties contribute to twice-daily
dosing regimen (25 mg dosage).
References
1) Davies?et al. (2007),?AZD6244(ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamics relationship, and potential for combination in preclinical models; Mol. Cancer Ther.,?6?2209
2) Yeh?et al. (2007),?Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor; Clin. Cancer Res.,?13?1576
3) Catalanotti?et al. (2013),?Phase II trial of MEK inhibitor selumetinib(AZD6244) in patients with BRAFV600E/K-mutated melanoma; Clin. Cancer Res.,?19?2257
4) O’Neil?et al. (2011),?Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma; J. Clin. Oncol.,?29?2350
5) Khurum?et al. (2012),?A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244)(MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors; J. Clin. Oncol.,?30?e13599
6) Hainsworth?et al. (2010),?A phase II, open label, randomized study to assess the efficacy and safety of AZD6244 versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens; J. Thorac. Oncol.,?5?1630
7) Bodoky?et al. (2012),?A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy; Invest. New Drugs,?30?1216
;