A research team led by Professor
s Kang Yell Choi in the Yonsei’s Department of Biotechnology has identified small molecules that inhibit growth of colorectal cancer (CRC) cells via degrading both b-catenin and Ras. The small molecules inhibiting the Wnt/b-catenin pathway were selected by screening of several small-molecule libraries. Among the 40 compounds initially identified by their inhibitory effects on the Wnt/b-catenin pathway reporter activity, KY1220 was selected as a compound that efficiently degrades both b-catenin and Ras without showing cytotoxicity. KY1220 effectively inhibited transformation of CRC cells with activated Wnt/b-catenin and Ras/ERK pathways by adenomatos polyposis coli (APC) and K-Ras mutations. By collaboration with Professor Gyoonhee Han from the Department of Biotechnology and Pharmacology, several hundreds of derivatives were obtained, and KYA1797K, a functionally improved compound retaining druggablity, was obtained.
KYA1797K effectively suppresses the growth of CRC cells with activated Wnt/β-catenin and Ras/ERK pathways. The RGS domain of axin was identified as a target for KYA1797K and molecular structure of RGS-axin-KYA1797K was determined by collaboration with Professor Weontae Lee in the Department of Biochemistry.
They further characterized that KYA1797K activates GSK3β by modulation of the b-catenin destruction complex. The activated GSK3β induces phosphorylation of both b-catenin and Ras, which is required for their polyubiquitin-dependent proteasomal degradation, via recruitment of the b-TrCP E3 linker protein. KYA1797K effectively suppressed growth of CRC in the xenograft mice transplanted with the CRC cells harboring both APC and K-Ras mutations. The effectiveness of KYA1797K was further shown by using the genetically engineered Apcmin/＋/KrasG12DLA2 mice harboring both APC and K-Ras mutations.
Their findings were published June 14, 2016 in the online edition of Nature Chemical Biology (1st author; Pu-Hyeon Cha). The title of the article is “Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation.” This study suggests that destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other types of cancers activated Wnt/β-catenin and Ras pathways.