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Inhibitors of\n ABL<\/jats:styled-content>\n tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long\u2010term treatment. An alternative approach to treat\n CML<\/jats:styled-content>\n is to downregulate the\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non\u2010genetic inhibitor of apoptosis protein [\n IAP<\/jats:styled-content>\n ]\u2010dependent Protein Erasers (\n SNIPER<\/jats:styled-content>\n ), which is designed to induce\n IAP<\/jats:styled-content>\n \u2010mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of\n SNIPER<\/jats:styled-content>\n (\n ABL<\/jats:styled-content>\n ) against\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n protein have been developed recently. In this study, we tested various combinations of\n ABL<\/jats:styled-content>\n inhibitors and\n IAP<\/jats:styled-content>\n ligands, and the linker was optimized for protein knockdown activity of\n SNIPER<\/jats:styled-content>\n (\n ABL<\/jats:styled-content>\n ). The resulting\n SNIPER<\/jats:styled-content>\n (\n ABL<\/jats:styled-content>\n )\u201039, in which dasatinib is conjugated to an\n IAP<\/jats:styled-content>\n ligand\n LCL<\/jats:styled-content>\n 161 derivative by polyethylene glycol (\n PEG<\/jats:styled-content>\n )\u00a0\u00d7\u00a03 linker, shows a potent activity to degrade the\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (\n cIAP<\/jats:styled-content>\n 1) and X\u2010linked inhibitor of apoptosis protein (\n XIAP<\/jats:styled-content>\n ) play a role in the degradation of\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n protein. Consistent with the degradation of\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n protein, the\n SNIPER<\/jats:styled-content>\n (\n ABL<\/jats:styled-content>\n )\u201039 inhibited the phosphorylation of signal transducer and activator of transcription 5 (\n STAT<\/jats:styled-content>\n 5) and Crk like proto\u2010oncogene (CrkL), and suppressed the growth of\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n \u2010positive\n CML<\/jats:styled-content>\n cells. These results suggest that\n SNIPER<\/jats:styled-content>\n (\n ABL<\/jats:styled-content>\n )\u201039 could be a candidate for a degradation\u2010based novel anti\u2010cancer drug against\n BCR<\/jats:styled-content>\n \u2010\n ABL<\/jats:styled-content>\n \u2010positive\n CML<\/jats:styled-content>\n .\n <\/jats:p>","DOI":"10.1111\/cas.13284","type":"journal-article","created":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T11:26:39Z","timestamp":1495797999000},"page":"1657-1666","source":"Crossref","is-referenced-by-count":97,"title":["Development of protein degradation inducers of oncogenic\n BCR<\/scp>\n \u2010\n ABL<\/scp>\n protein by conjugation of\n ABL<\/scp>\n kinase inhibitors and\n IAP<\/scp>\n ligands"],"prefix":"10.1111","volume":"108","author":[{"given":"Norihito","family":"Shibata","sequence":"first","affiliation":[{"name":"Division of Molecular Target and Gene Therapy Products National Institute of Health Sciences Tokyo 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