Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cell	168	5	2017 Feb 23	878-889.e29	Cell

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) 10	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 G13D	adult T-cell leukemia/lymphoma	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
NRAS G13V	adult T-cell leukemia/lymphoma	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