A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

Sai Krishna Athuluri-Divakar; Rodrigo Vasquez-Del Carpio; Kaushik Dutta; Stacey J. Baker; Stephen C. Cosenza; Indranil Basu; Yogesh K. Gupta; M. V.Ramana Reddy; Lynn Ueno; Jonathan R. Hart; Peter K. Vogt; David Mulholland; Chandan Guha; Aneel K. Aggarwal; E. Premkumar Reddy

doi:10.1016/j.cell.2016.03.045

A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

Sai Krishna Athuluri-Divakar, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J. Baker, Stephen C. Cosenza, Indranil Basu, Yogesh K. Gupta, M. V.Ramana Reddy, Lynn Ueno, Jonathan R. Hart, Peter K. Vogt, David Mulholland, Chandan Guha, Aneel K. Aggarwal, E. Premkumar Reddy

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

208 Scopus citations

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.

Original language	English (US)
Pages (from-to)	643-655
Number of pages	13
Journal	Cell
Volume	165
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2016.03.045
State	Published - Apr 21 2016

Keywords

MAPK
PI3K
RAF
RAS
RAS-binding domain
rigosertib

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2016.03.045

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Athuluri-Divakar, S. K., Vasquez-Del Carpio, R., Dutta, K., Baker, S. J., Cosenza, S. C., Basu, I., Gupta, Y. K., Reddy, M. V. R., Ueno, L., Hart, J. R., Vogt, P. K., Mulholland, D., Guha, C., Aggarwal, A. K., & Reddy, E. P. (2016). A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell, 165(3), 643-655. https://doi.org/10.1016/j.cell.2016.03.045

Athuluri-Divakar, SK, Vasquez-Del Carpio, R, Dutta, K, Baker, SJ, Cosenza, SC, Basu, I, Gupta, YK, Reddy, MVR, Ueno, L, Hart, JR, Vogt, PK, Mulholland, D, Guha, C, Aggarwal, AK & Reddy, EP 2016, 'A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling', Cell, vol. 165, no. 3, pp. 643-655. https://doi.org/10.1016/j.cell.2016.03.045

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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.",

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AU - Athuluri-Divakar, Sai Krishna

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AU - Baker, Stacey J.

AU - Cosenza, Stephen C.

AU - Basu, Indranil

AU - Gupta, Yogesh K.

AU - Reddy, M. V.Ramana

AU - Ueno, Lynn

AU - Hart, Jonathan R.

AU - Vogt, Peter K.

AU - Mulholland, David

AU - Guha, Chandan

AU - Aggarwal, Aneel K.

AU - Reddy, E. Premkumar

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N2 - 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.

AB - 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.

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A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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