Arresting kinase suppressor of Ras in an inactive state
© The Author(s) 2017
Received: 31 October 2016
Accepted: 17 November 2016
Published: 9 January 2017
Ras protein signaling pathways are important in controlling the plight of different types of cancer. Here we discussed the paper entitled “Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling” published in Nature journal on inactivating the kinase suppressor of Ras (KSR) protein using a small molecule as an inhibitor by Dhawan et al. A biphenyl ether analogue of a quinazoline binds in one of the binding pockets of KSR and results in stabilization of its inactive state. In this inactive state, KSR is unable to take part in the cascade of protein association to perform the signalling process.
KeywordsRas Cancer Quinazoline analogues Structure–activity relationship Kinase inhibitors
Ras proteins are a small guanine nucleotide-hydrolyzing proteins that play important roles in cell growth and spread in the mitogen-activated protein kinase (MAPK) signaling pathway . Ras is the most mutated gene that is involved in almost one-third of all cancers [2, 3]. The kinase suppressor of Ras (KSR) works as a scaffold for the Ras/MAPK pathway [4, 5]. A number of studies have been conducted to target RAS protein using small molecules as inhibitors . These studies includes the nucleotide exchange blockage [6, 7], Ras association with son of sevenless homologue (SOS) [8–10], and Ras–Raf interaction [11, 12]. In the past, some approaches were used to target Ras via the KSR due to its pseudokinase standing and non-catalytic function, but now it is a more favorable targeted pathway for designing drugs [13, 14]. The RAS–RAF–KSR–MEK1 pathway proteins work in a cascade. Each protein in this pathway offer an opportunity to target the Ras mutation-related cancers by developing more powerful therapeutics [15–17]. In one of the study, a small molecule called rigosertib, which is a styryl-benzyl sulfone binds with a Ras-binding domain (RBD) and causes the dissociation of RAS and RAF, resulting in inhibition of the RAS–RAF–MEK pathway .
Dhawan et al.  resolved the crystal structure of KSR2–MEK1 with APS-2-79. The APS-2-79 luckly hold the same binding pocket like that of ATP within the KSR2 protein in the KSR2–MEK1 complex. Inside the binding pocket, the terminal phenyl ring of biphenyl ether group of APS-2-79 makes π-stacking interactions with Phe725, Tyr714, and Phe804 of KSR2. Removal of this phenyl side group from the main compounds leads to inactivity and loss of competitive ability for the binding pocket and that is why this side group makes it highly selective for KSR2. A hydrogen bond also exists between N-1 of quinazoline of APS-2-79 and Cys742 of KSR2. Dhawan et al.  concluded that by binding APS-2-79 in the KSR2 pocket and making complex with MEK1, this complexation causes deep burying of the Ser218 and Ser222 of MEK1 oncoprotein. Thus, these two serine residues of MEK1 are not available for phorophorylation by RAF, resulting in the inhibition of signaling. The APS-2-79 arrest the KSR2-MEK1 into an inactive state, resulting in an off state of the complex, and heterodimerization of KSR–RAF is not possible. This inhibition of RAF–KSR dimerization was further confirmed by mutagenic tests.
The use of small-molecule inhibitors that interact with different kinases and pseduokinases, especially the RAS pathway proteins, is a promising strategy for cancer cure. Similarly, due to continuous drug resistance, structure-based drug design and covalent binding inhibitors for RAS signaling pathways should also be considered [18, 19].
SLB and YM wrote this commentary together. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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- Moorthy NS, Sousa SF, Ramos MJ, Fernandes PA. Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors. J Enzym Inhib Med Chem. 2011;26:777–91.View ArticleGoogle Scholar
- Jarvis LM. Have drug hunters finally cracked KRas? Chem Eng News. 2016;94:28–33.Google Scholar
- Ostrem J, Shokat K. Direct small-molecule inhibitors of K-Ras: from structural insights to mechanism-based design. Nat Publ Gr. 2016;15:771–85.Google Scholar
- Nguyen A, Burack WR, Stock JL, Kortum R, Chaika OV, Afkarian M, Muller WJ, Murphy KM, Morrison DK, Lewis RE, McNeish J, Shaw AS. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol Cell Biol. 2002;22:3035–45.View ArticlePubMedPubMed CentralGoogle Scholar
- Clapéron A, Therrien M. KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene. 2007;26:3143–58.View ArticlePubMedGoogle Scholar
- Hocker HJ, Cho KJ, Chen CY, Rambahal N, Sagineedu SR, Shaari K, Stanslas J, Hancock JF, Gorfe AA. Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc Natl Acad Sci USA. 2013;110(25):10201–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351:604–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ, Skelton NJ, Fauber BP, Pan B, Malek S, Stokoe D, Ludlam MJC, Bowman KK, Wu J, Giannetti AM, Starovasnik MA, Mellman I, Jackson PK, Rudolph J, Wang W, Fang G. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA. 2012;109:5299–304.View ArticlePubMedPubMed CentralGoogle Scholar
- Burns MC, Sun Q, Daniels RN, Camper D, Kennedy JP, Phan J, Olejniczak ET, Lee T, Waterson AG, Rossanese OW, Fesik SW. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci USA. 2014;111:3401–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Sun Q, Burke JP, Phan J, Burns MC, Olejniczak ET, Waterson AG, Lee T, Rossanese OW, Fesik SW. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew Chemie. 2012;51:6140–3.View ArticleGoogle Scholar
- Waldmann H, Karaguni IM, Carpintero M, Gourzoulidou E, Herrmann C, Brockmann C, Oschkinat H, Müller O. Sulindac-derived Ras pathway inhibitors target the Ras–Raf interaction and downstream effectors in the Ras pathway. Angew Chemie. 2004;43:454–8.View ArticleGoogle Scholar
- Pan MR, Chang HC, Hung WC. Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c–Raf interaction and activation of MAP kinase phosphatases. Cell Signal. 2008;20:1134–41.View ArticlePubMedGoogle Scholar
- 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. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell. 2016;165:643–55.View ArticlePubMedPubMed CentralGoogle Scholar
- Dhawan NS, Scopton AP, Dar AC. Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling. Nature. 2016;537:112–6.View ArticlePubMedGoogle Scholar
- Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447:864–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Target. 2012;16:103–19.View ArticleGoogle Scholar
- Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo P, Ruvolo V, Evangelisti C, Martelli AM, McCubrey JA. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia. 2011;25:1080–94.View ArticlePubMedGoogle Scholar
- Badshah S, Mabkhot Y. Commentary: the search for covalently ligandable proteins in biological systems. Molecules. 2016;21:1170.View ArticleGoogle Scholar
- Hunter JC, Gurbani D, Ficarro SB, Carrasco MA, Lim SM, Choi HG, Xie T, Marto JA, Chen Z, Gray NS, Westover KD. In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. Proc Natl Acad Sci. 2014;111:8895–900.View ArticlePubMedPubMed CentralGoogle Scholar