Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. Issue 20 (15th October 2016)

• Record Type: Journal Article
• Authors: Demizu, Yosuke; Shibata, Norihito; Hattori, Takayuki; Ohoka, Nobumichi; Motoi, Hiromi; Misawa, Takashi; Shoda, Takuji; Naito, Mikihiko; Kurihara, Masaaki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 20(2016)
• Page Start: 4865
• Page End: 4869
• Publication Date: 2016-10-15
• Subjects: BCR-ABL -- Bestatin -- Imatinib -- E3 ubiquitin ligase -- Protein knockdown; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.09.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.