We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
INTEGRA BIOSCIENCES AG

Download Mobile App




Experimental Small-Molecule Anticancer Drug Blocks RAS-binding Domains

By LabMedica International staff writers
Posted on 04 May 2016
Print article
The experimental small-molecule anticancer drug rigosertib was shown to block tumor growth by acting as an RAS-mimetic and interacting with the RAS binding domains of RAF kinases, resulting in their inability to bind to RAS, which inhibited the RAS-RAF-MEK pathway.

Oncogenic activation of RAS genes due to point mutations occurs in 20%–30% of human cancers. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules would seem to be an attractive therapeutic approach.

Investigators at the Icahn School of Medicine at Mount Sinai (New York, NY, USA) reported in the April 21, 2016, issue of the journal Cell that the experimental drug rigosertib, a styryl-benzyl sulfone, acted as a RAS-mimetic and interacted with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway.

RAF kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. RAF is an acronym for Rapidly Accelerated Fibrosarcoma. RAF kinases participate in the RAS-RAF-MEK-ERK signal transduction cascade, also referred to as the mitogen-activated protein kinase (MAPK) cascade. Activation of RAF kinases requires interaction with RAS-GTPases.

ERKs (extracellular-signal-regulated kinases or classical MAP kinases) are widely expressed protein kinase intracellular signaling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

MEK (mitogen/extracellular signal-regulated kinase) is a member of the MAPK signaling cascade that is activated in some cancers. When MEK is inhibited, cell proliferation is blocked and apoptosis (controlled cell death) is induced.

The investigators also found that rigosertib bound to the RBDs of Ral-GDS (Ral guanine nucleotide dissociation stimulator) and PI3Ks (phosphatidylinositol-3-kinases), results indicating that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

"This discovery is a significant breakthrough for the cancer field," said senior author Dr. E. Premkumar Reddy, professor of oncological sciences at the Icahn School of Medicine at Mount Sinai. "Rigosertib's mechanism of action represents a new paradigm for attacking the intractable RAS oncogenes. Our current focus is to use the information from our studies with rigosertib to design the next generation of small molecule RAS-targeting therapies, and we are excited to have recently identified several compounds which we think improve on the qualities of rigosertib."

Related Links:
Icahn School of Medicine at Mount Sinai

Platinum Member
COVID-19 Rapid Test
OSOM COVID-19 Antigen Rapid Test
HLX
Complement 3 (C3) Test
GPP-100 C3 Kit
New
Gold Member
Fully Automated Cell Density/Viability Analyzer
BioProfile FAST CDV

Print article

Channels

Clinical Chemistry

view channel
Image: Reaching speeds up to 6,000 RPM, this centrifuge forms the basis for a new type of inexpensive, POC biomedical test (Photo courtesy of Duke University)

POC Biomedical Test Spins Water Droplet Using Sound Waves for Cancer Detection

Exosomes, tiny cellular bioparticles carrying a specific set of proteins, lipids, and genetic materials, play a crucial role in cell communication and hold promise for non-invasive diagnostics.... Read more

Molecular Diagnostics

view channel
Image: The study showed the blood-based cancer screening test detects 83% of people with colorectal cancer with specificity of 90% (Photo courtesy of Guardant Health)

Blood Test Shows 83% Accuracy for Detecting Colorectal Cancer

Colorectal cancer is the second biggest cause of cancer deaths among adults in the U.S., with forecasts suggesting 53,010 people might die from it in 2024. While fewer older adults are dying from this... Read more

Hematology

view channel
Image: The Gazelle Hb Variant Test (Photo courtesy of Hemex Health)

First Affordable and Rapid Test for Beta Thalassemia Demonstrates 99% Diagnostic Accuracy

Hemoglobin disorders rank as some of the most prevalent monogenic diseases globally. Among various hemoglobin disorders, beta thalassemia, a hereditary blood disorder, affects about 1.5% of the world's... Read more

Microbiology

view channel
Image: The new platform is designed to perform blood-based diagnoses of nontuberculosis mycobacteria (Photo courtesy of 123RF)

New Blood Test Cuts Diagnosis Time for Nontuberculous Mycobacteria Infections from Months to Hours

Breathing in nontuberculous mycobacteria (NTM) is a common experience for many people. These bacteria are present in water systems, soil, and dust all over the world and usually don't cause any problems.... Read more

Industry

view channel
Image: These new assays are being developed for use on the recently introduced DxI 9000 Immunoassay Analyzer (Photo courtesy of Beckman Coulter)

Beckman Coulter and Fujirebio Expand Partnership on Neurodegenerative Disease Diagnostics

Beckman Coulter Diagnostics (Brea, CA, USA) and Fujirebio Diagnostics (Tokyo, Japan) have expanded their partnership focused on the development, manufacturing and clinical adoption of neurodegenerative... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.