Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway.
The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquitin-proteasome pathway. In this study, we designed and synthesized novel small molecules called SNIPER(TACC3)s, which target the spindle regulatory protein transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3 and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/C(CDH1) mediates the SNIPER(TACC3)-induced degradation of TACC3. Intriguingly, SNIPER(TACC3) selectively induced cell death in cancer cells expressing a larger amount of TACC3 protein than normal cells. These results suggest that protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy for treating cancers overexpressing the TACC3 protein.
Division of Biochemistry and Molecular Biology, National Institute of Health Science, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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Ohoka
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan.
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Nagai
Division of Biochemistry and Molecular Biology, National Institute of Health Science, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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Hattori
Division of Biochemistry and Molecular Biology, National Institute of Health Science, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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Okuhira
Division of Biochemistry and Molecular Biology, National Institute of Health Science, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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Shibata
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan.
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Cho
Division of Biochemistry and Molecular Biology, National Institute of Health Science, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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Naito
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D055646:Killer Factors, Yeast / Q000737:chemistry; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D000970:Antineoplastic Agents; D055646:Killer Factors, Yeast; D008869:Microtubule-Associated Proteins; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; C120551:TACC3 protein, human; D025801:Ubiquitin; C065919:KHR protein, S cerevisiae; D046988:Proteasome Endopeptidase Complex; D007930:Leucine; C012211:ubenimex