Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib
- Resource Type
- Authors
- Chen Yiyi; Xicheng Yang; Yulong Xu; Linqian Yu; Qiong Xie; Hao Chen; Wei Li; Liming Shao; Huijiao Sun
- Source
- Bioorganic & Medicinal Chemistry Letters. 28:2148-2152
- Subject
- Models, Molecular
0301 basic medicine
Proteasome Endopeptidase Complex
Clinical Biochemistry
Pharmaceutical Science
Crystallography, X-Ray
Scaffold hopping
Topology
01 natural sciences
Biochemistry
20s proteasome
Bortezomib
Structure-Activity Relationship
03 medical and health sciences
Drug Discovery
medicine
Humans
Molecular Biology
Topology (chemistry)
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
Metabolic stability
0104 chemical sciences
030104 developmental biology
Proteasome
Molecular Medicine
Proteasome Inhibitors
medicine.drug
- Language
- ISSN
- 0960-894X
A series of structurally novel proteasome inhibitors 1 – 12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC 50 = 9.7 nM) to bortezomib (IC 50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.