Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation.
Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating β-catenin and Ras degradation through enhancement of the β-catenin destruction complex activating GSK3β. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/β-catenin and Ras pathways.
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Pu-Hyeon
PH
Cha
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Yong-Hee
YH
Cho
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Sang-Kyu
SK
Lee
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
JaeHeon
J
Lee
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Woo-Jeong
WJ
Jeong
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Byoung-San
BS
Moon
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Ji-Hye
JH
Yun
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Jee Sun
JS
Yang
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Sooho
S
Choi
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Juyong
J
Yoon
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Hyun-Yi
HY
Kim
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Mi-Yeon
MY
Kim
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Saluja
S
Kaduwal
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Weontae
W
Lee
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea.
Do Sik
do S
Min
Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
Hoguen
H
Kim
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Gyoonhee
G
Han
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Kang-Yell
KY
Choi
D000818:Animals; D060466:Axin Protein / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017491:Genes, APC; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013867:Thiohydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
C555451:AXIN1 protein, human; D060466:Axin Protein; C000617986:KY1220; D020710:RGS Proteins; D054852:Small Molecule Libraries; D013867:Thiohydantoins; D051176:beta Catenin; D016283:Proto-Oncogene Proteins p21(ras)