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Cell. 2017 Feb 23;168(5):878-889.e29. doi: 10.1016/j.cell.2017.02.006.

Multivalent Small-Molecule Pan-RAS Inhibitors.

Author information

1
Department of Chemistry, Columbia University, New York, NY 10027, USA.
2
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
3
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Division of Digestive and Liver Diseases in the Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
5
Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY 10027, USA.
6
Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA.
7
Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA.
8
Department of Biological Sciences, St. John's University, Queens, NY 11439, USA.
9
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
10
Department of Chemistry, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.

Abstract

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.

KEYWORDS:

GTPase; Hras; Kras; Nras; Ras; cancer; chemical biology; drug design; multivalent; small molecule

PMID:
28235199
PMCID:
PMC5362268
DOI:
10.1016/j.cell.2017.02.006
[Indexed for MEDLINE]
Free PMC Article

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