Details

Autor(en) / Beteiligte

• Demizu, Yosuke
• Shibata, Norihito
• Hattori, Takayuki
• Ohoka, Nobumichi
• Motoi, Hiromi
• Misawa, Takashi
• Shoda, Takuji
• Naito, Mikihiko
• Kurihara, Masaaki

Titel

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

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2016-10, Vol.26 (20), p.4865-4869

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• [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.