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Ref Type Journal Article
PMID (28235199)
Authors Welsch ME, Kaplan A, Chambers JM, Stokes ME, Bos PH, Zask A, Zhang Y, Sanchez-Martin M, Badgley MA, Huang CS, Tran TH, Akkiraju H, Brown LM, Nandakumar R, Cremers S, Yang WS, Tong L, Olive KP, Ferrando A, Stockwell BR
Title Multivalent Small-Molecule Pan-RAS Inhibitors.
Journal Cell
Vol 168
Issue 5
Date 2017 Feb 23
URL
Abstract Text Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
3144 RAS Inhibitor (Pan) 8 3144 is a Pan-RAS inhibitor, which binds to KRAS, NRAS, and HRAS proteins and decreases RAS-mediated signaling, and may reduce growth of RAS-dependent tumors (PMID: 28235199).
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
NRAS G13V adult T-cell leukemia sensitive 3144 Preclinical - Pdx & cell culture Actionable In a preclinical study, 3144 inhibited growth of patient-derived T-cell acute lymphocytic leukemia cells harboring NRAS G13V in culture, and reduced tumor burden in xenograft models (PMID: 28235199). 28235199
NRAS G13D adult T-cell leukemia sensitive 3144 Preclinical - Cell culture Actionable In a preclinical study, 3144 inhibited growth of patient-derived T-cell acute lymphocytic leukemia cells harboring NRAS G13D in culture (PMID: 28235199). 28235199