Structural optimization of novel Ras modulator for treatment of Colorectal cancer by promoting β-catenin and Ras degradation

Seonghwi Choi, Hyuntae Kim, Won Ji Ryu, Kang Yell Choi, Taegun Kim, Doona Song, Gyoonhee Han

Research output: Contribution to journalArticlepeer-review


Ras protein has been considered a fascinating target for anticancer therapy because its malfunction is closely related to cancer. However, Ras has been considered undruggable because of the failure to regulate its malfunction by controlling the Ras activation mechanism. Recently, Lumakras targeting the G12C mutation was approved, and therapeutic interest in Ras for anticancer therapy has been rejuvenated. Here, we present a series of compounds that inhibit Ras via a unique mechanism of action that exploits the relationship between the Wnt/β-catenin pathway and Ras. KYA1797K (1) binds to axin to stabilize the β-catenin destruction complex that causes the phosphorylation and subsequent degradation of Ras, similar to canonical β-catenin regulation. Based on the chemical structure of 1, we performed a structural optimization and identified 3-(2-hydroxyethyl)-5-((6-(4-nitrophenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (13d) as the most potent compound. 13d displayed antitumor effects in a colorectal cancer model with enhanced inhibition activity on Ras. The results of this study suggest that the further development of 13d could contribute to the development of Ras inhibitors with novel mechanisms of action.

Original languageEnglish
Article number106234
JournalBioorganic Chemistry
Publication statusPublished - 2023 Jan

Bibliographical note

Funding Information:
This research was supported by a grant from Translational Research Center for Protein Function Control (TRCP) funded by the Ministry of Science, ICT and Future Planning (MSIP) of Korea [NRF-2009-0083522 and NRF-2016R1A5A1004694], the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [HI14C1324], Ministry of Science and ICT [NRF-2019M3E5D5066690] and Bio & Medical Technology Development Program of the National Research Foundation (NRF)& funded by the Korean government (MSIP&MOHW) [2016M3A9B5941215].

Publisher Copyright:
© 2022 The Author(s)

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry


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