jm9b01264_si_001.pdf (776.72 kB)
Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
journal contribution
posted on 2019-10-02, 12:08 authored by Quanju Zhao, Chaowei Ren, Linyi Liu, Jinju Chen, Yubao Shao, Ning Sun, Renhong Sun, Ying Kong, Xinyu Ding, Xianfang Zhang, Youwei Xu, Bei Yang, Qianqian Yin, Xiaobao Yang, Biao JiangThe
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 SIAIS178 (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 SIAIS178 as efficacious BCR-ABL degrader warrants
extensive further investigation for the treatment of BCR-ABL+ leukemia.