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

• Published in: Journal of medicinal chemistry Vol. 62; no. 20; pp. 9281 - 9298
• Main Authors: Zhao, Quanju, Ren, Chaowei, Liu, Linyi, Chen, Jinju, Shao, Yubao, Sun, Ning, Sun, Renhong, Kong, Ying, Ding, Xinyu, Zhang, Xianfang, Xu, Youwei, Yang, Bei, Yin, Qianqian, Yang, Xiaobao, Jiang, Biao
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.2019; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; INDUCED PROTEIN-DEGRADATION; CONJUGATION; STEM-CELLS; CHIMERIC MOLECULES; RESISTANCE; KINASE INHIBITORS; MUTATIONS; PROTAC DESIGN; BROMODOMAIN; CHRONIC MYELOID-LEUKEMIA
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01264

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.