Reference Detail

Ref Type Journal Article
PMID (27820802)
Authors Spencer-Smith R, Koide A, Zhou Y, Eguchi RR, Sha F, Gajwani P, Santana D, Gupta A, Jacobs M, Herrero-Garcia E, Cobbert J, Lavoie H, Smith M, Rajakulendran T, Dowdell E, Okur MN, Dementieva I, Sicheri F, Therrien M, Hancock JF, Ikura M, Koide S, O'Bryan JP
Title Inhibition of RAS function through targeting an allosteric regulatory site.
Journal Nature chemical biology
Vol 13
Issue 1
Date 2017 Jan
URL
Abstract Text RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the α4-β6-α5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the α4-β6-α5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
NS1 NS1 is a synthetic monobody that binds to GTP and GDP states of HRAS and KRAS, thereby inhibiting RAS dimerization and subsequent RAF activity, which may result in inhibition of cell transformation (PMID: 27820802).
Drug Name Trade Name Synonyms Drug Classes Drug Description
NS1 HRAS Inhibitor 1 KRAS Inhibitor 2 NS1 is a synthetic monobody that binds to GTP and GDP states of HRAS and KRAS, thereby inhibiting RAS dimerization and subsequent RAF activity, which may result in inhibition of cell transformation (PMID: 27820802).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS mutant Advanced Solid Tumor sensitive NS1 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing a KRAS mutation demonstrated sensitivity to NS1 in culture, resulting in decreased Mapk and Akt signaling and inhibition of cell transformation (PMID: 27820802). 27820802
NRAS mutant Advanced Solid Tumor no benefit NS1 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing an NRAS mutation did not respond to treatment with NS1 in culture, resulting in sustained downstream signaling and cell transformation (PMID: 27820802). 27820802
HRAS Q61L bladder carcinoma sensitive NS1 Preclinical - Cell culture Actionable In a preclinical study, bladder carcinoma cells expressing HRAS Q61L demonstrated sensitivity to NS1, resulting in inhibition of Mapk signaling and cell proliferation in culture (PMID: 27820802). 27820802