期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 20, 页码 9281-9298出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01264
关键词
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资金
- National Natural Science Foundation of China (NSFC) [81702600]
- Shanghai Sailing Program [17YF1412200]
- Shanghai Natural Science Foundation [19ZR1433600]
- China Postdoctoral Science Foundation [2018M642112, 2018M642110, 2018M632181, 2019M651609]
- Jing Medicine Technology Ltd.
The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIA15178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL(+) leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAI5178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL(+) leukemia.
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