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SIAIS178 is a potent BCR-ABL Degrader. SIAIS178 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.

SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology with an IC50 of 24 nM. SIAIS178 causes effective degradation of BCR-ABL protein by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. SIAIS178 has anticancer activity[1].

VHL; Bcr-Abl: 24 nM (IC₅₀)

[1] Zhao Q, et al. Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase. J Med Chem. 2019 Oct 24;62(20):9281-9298. DOI:10.1021/acs.jmedchem.9b01264