Identification of Ras-degrading small molecules that inhibit the transformation of colorectal cancer cells independent of β-catenin signaling

Wookjin Shin, Sang Kyu Lee, Jeong Ha Hwang, Jong Chan Park, Yong Hee Cho, Eun Ji Ro, Yeonhwa Song, Haeng Ran Seo, Kang Yell Choi

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9 Citations (Scopus)


Although the development of drugs that control Ras is an emerging topic in cancer therapy, no clinically applicable drug is currently available. We have previously utilized knowledge of the Wnt/β-catenin signaling-dependent mechanism of Ras protein stability regulation to identify small molecules that inhibit the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both β-catenin and Ras. Due to the absence of Ras degradation in cells expressing a nondegradable mutant form of β-catenin and the need to determine an alternative mechanism of Ras degradation, we designed a cell-based system to screen compounds that degrade Ras independent of the Wnt/β-catenin signaling pathway. A cell-based high-content screening (HCS) system that monitors the levels of EGFP-K-Ras G12V was established using HCT-116 cells harboring a nondegradable mutant CTNNB1 (ΔS45). Through HCS of a chemical library composed of 10,000 compounds and subsequent characterization of hits, we identified several compounds that degrade Ras without affecting the β-catenin levels. KY7749, one of the most effective compounds, inhibited the proliferation and transformation of CRC cells, especially KRAS-mutant cells that are resistant to the EGFR monoclonal antibody cetuximab. Small molecules that degrade Ras independent of β-catenin may able to be used in treatments for cancers caused by aberrant EGFR and Ras.

Original languageEnglish
Article number71
JournalExperimental and Molecular Medicine
Issue number6
Publication statusPublished - 2018 Jun 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (grants 2016R1A5A1004694 and 2015R1A2A1A05001873; to K.Y. Choi). We thank Dr. B. Vogelstein and K.W. Kinzler for providing the DLD-1 isogenic cells. We also thank Dr. W. Namkung for providing the small molecule library and Dr. I. Kim for helpful discussions related to the high-content screening procedure.

Publisher Copyright:
© 2018 The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


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