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|Ref Type||Journal Article|
|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|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|NS1||HRAS Inhibitor 1 KRAS Inhibitor 6||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, PMID: 29072601).|
|Gene||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|
|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|
|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|