Repositioning Candidate Details

Candidate ID: R1390
Source ID: DB11689
Source Type: approved; investigational
Compound Type: small molecule
Compound Name: Selumetinib
Synonyms: --
Molecular Formula: C17H15BrClFN4O3
SMILES: CN1C=NC2=C(F)C(NC3=C(Cl)C=C(Br)C=C3)=C(C=C12)C(=O)NOCCO
Structure:
DrugBank Description: Activation of the Raf-MEK-ERK signaling pathway is known to be implemented in several types of malignancies, thus, mitogen-activated protein kinase kinase (MEK) inhibitors such as selumetinib are important tools that can target the problematic overactivity of this pathway. Results from clinical trials investigating earlier developed MEK inhibitors were underwhelming. However, selumetinib demonstrated impressive efficacy and tolerability in Phase I trials, leading to its continued investigation for the treatment of various types of tumors in Phase II trials. Currently, the novel MEK 1 / 2 inhibitor, selumetinib, is approved solely for the treatment of Neurofibromatosis type 1 (NF-1) in a limited age group. NF-1 is considered rare with an estimated incidence of 1/3000 individuals. It is a genetic, autosomal dominant condition resulting from mutations of the NF1 gene, which can lead to various complications including the development of multiple tumors in the nervous system. Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered to be relatively uncommon compared to other variants of NF-1. Luckily, the use of selumetinib in patients with NF-1 has shown efficacy in shrinking associated tumors and is linked to other positive clinical outcomes.
CAS Number: 606143-52-6
Molecular Weight: 457.68
DrugBank Indication: Although selumetinib has been investigated for the treatment of several types of cancer, it is currently only indicated for the treatment of neurofibromatosis type 1 (NF1) in patients ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN).
DrugBank Pharmacology: Selumetinib is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported. Selumetinib has minimal off-target activity, contributing to its impressive safety profile.
DrugBank MoA: The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets. As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction.
Targets: Dual specificity mitogen-activated protein kinase kinase 1 inhibitor; Dual specificity mitogen-activated protein kinase kinase 2 inhibitor
Inclusion Criteria: Therapeutic strategy associated