Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase

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 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.