Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.

Abstract

We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

• Authors: Zachary Miller, Keun-Sik Kim, Do-Min Lee, Vinod Kasam, Si Eun Baek, Kwang Hyun Lee, Yan-Yan Zhang, Lin Ao, Kimberly Carmony, Na-Ra Lee, Shou Zhou, Qingquan Zhao, Yujin Jang, Hyun-Young Jeong, Chang-Guo Zhan, Wooin Lee, Dong-Eun Kim, Kyung Bo Kim
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 4 Pg. 2036-41 (Feb 26 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25658656 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Proteasome Inhibitors
• Pyrazoles
• Small Molecule Libraries
• pyrazole
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Catalytic Domain (drug effects)
• Cell Proliferation (drug effects)
• Computer Simulation
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Humans
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Molecular Structure
• Neoplasms, Experimental (drug therapy, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors (administration & dosage, chemistry, pharmacology)
• Pyrazoles (administration & dosage, chemistry, pharmacology)
• Small Molecule Libraries (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured