Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 20; pp. 4865 - 4869
• Main Authors: Demizu, Yosuke, Shibata, Norihito, Hattori, Takayuki, Ohoka, Nobumichi, Motoi, Hiromi, Misawa, Takashi, Shoda, Takuji, Naito, Mikihiko, Kurihara, Masaaki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2016; Elsevier
• Subjects: BCR-ABL; Bestatin; Chemistry; Chemistry, Medicinal; Chemistry, Organic; E3 ubiquitin ligase; Fusion Proteins, bcr-abl - metabolism; Humans; Imatinib; Imatinib Mesylate - metabolism; Inhibitor of Apoptosis Proteins - metabolism; K562 Cells; Life Sciences & Biomedicine; Ligands; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Protein knockdown; Proteolysis; Science & Technology; Protein knockdown; Imatinib; E3 ubiquitin ligase; Bestatin; BCR-ABL; DESIGN; HYBRID MOLECULES; TYROSINE KINASE; ALPHA; CHRONIC MYELOID-LEUKEMIA; CELL-DEATH; SMALL-MOLECULE PROTACS; UBIQUITINATION; PHILADELPHIA-CHROMOSOME
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2016.09.041

[Display omitted] The manipulation of protein stability with small molecules has great potential as a technique for aiding the development of clinical therapies, including treatments for cancer. In this study, BCR-ABL protein degradation inducers called SNIPER(ABL) (Specific and Non-genetic inhibitors of apoptosis protein [IAP]-dependent Protein Erasers) were developed. The designed molecules contained two biologically active scaffolds: one was an imatinib derivative that binds to BCL-ABL and the other was a methyl bestatin that binds to cellular IAP 1 (cIAP1). The hybrid molecules, SNIPER(ABL), were expected to recruit BCR-ABL to cIAP1 for removal by proteasomes. In fact, SNIPER(ABL) induced the degradation of BCR-ABL protein and a subsequent reduction in cell growth. Thus, the degradation of BCR-ABL by SNIPER(ABL) is one potential strategy for treating BCR-ABL driven chronic myelogenous leukemia.