Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand.
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.
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan. Electronic address: demizu@nihs.go.jp.
Yosuke
Y
Demizu
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan.
Norihito
N
Shibata
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan.
Takayuki
T
Hattori
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan.
Nobumichi
N
Ohoka
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.
Hiromi
H
Motoi
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.
Takashi
T
Misawa
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.
Takuji
T
Shoda
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan. Electronic address: miki-naito@nihs.go.jp.
Mikihiko
M
Naito
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan. Electronic address: masaaki@nihs.go.jp.
Masaaki
M
Kurihara
D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D020014:K562 Cells; D008024:Ligands; D011485:Protein Binding; D059748:Proteolysis
D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
BCR-ABL; Bestatin; E3 ubiquitin ligase; Imatinib; Protein knockdown