Experimental Small-Molecule Anticancer Drug Blocks RAS-binding Domains

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."

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