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A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling
Sai Krishna Athuluri-Divakar1, Rodrigo Vasquez-Del Carpio1, Kaushik Dutta2
1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Abstract:
Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. 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 constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts 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. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.
Insights
Rigosertib, a novel drug, inhibits cancer-driving RAS signaling by blocking interactions with RAS-binding domains (RBDs). This disruption affects key pathways like RAS-RAF-MEK, offering a new therapeutic strategy for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS gene mutations are common drivers in 20%-30% of human cancers.
- Targeting RAS oncogenic proteins is a significant challenge in cancer therapy.
- RAS signaling relies on interactions with effector proteins via RAS-binding domains (RBDs).
Purpose of the Study:
- To investigate rigosertib as a potential inhibitor of RAS signaling.
- To determine the mechanism by which rigosertib affects RAS-effector interactions.
- To explore rigosertib's efficacy in disrupting key oncogenic pathways.
Main Methods:
- In vitro studies using rigosertib, a styryl-benzyl sulfone.
- Analysis of rigosertib's interaction with RAS-binding domains (RBDs) of effector proteins.
- Assessment of downstream signaling pathway inhibition, including RAS-RAF-MEK.
Main Results:
- Rigosertib acts as a RAS-mimetic, binding to RBDs of RAF kinases.
- This binding prevents RAS interaction with RAF, inhibiting RAF activation and the RAS-RAF-MEK pathway.
- Rigosertib also binds to RBDs of Ral-GDS and PI3Ks, indicating broader pathway inhibition.
Conclusions:
- Rigosertib effectively inhibits RAS signaling by targeting RBDs.
- The drug disrupts multiple oncogenic signaling pathways, including RAS-RAF-MEK, Ral-GDS, and PI3K.
- Targeting RBDs with rigosertib presents a promising therapeutic strategy for RAS-driven cancers.
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