报告题目: Potent and Selective Piperidinone Inhibitors of the MDM2-p53 Interaction: Discovery to the Clinic
报告人: Daqing Sun (孙大庆) daqings@amgen.com
Principal Scientist of Medicinal Chemistry, Amgen SF, USA
报告时间: 2013年12月27日（星期五）上午9：30-11：00
报告地点：独墅湖校区701号楼B501室
报告摘要: The tumor suppressor protein p53 plays a pivotal role in protecting cells from malignant transformation. It activates the transcription of numerous genes involved in cell cycle arrest, DNA repair, senescence, and apoptosis. Recent studies demonstrate that restoring endogenous p53 function causes tumor regression in vivo and is a promising approach for the treatment of cancer.
This presentation will describe a successful approach for designing new scaffolds of MDM2 inhibitors based on the binding mode of known inhibitors with MDM2 protein. Through a combination of X-ray crystallography, molecular modeling, and iterative medicinal chemistry, we have identified highly potent, selective MDM2 inhibitors with remarkable pharmacokinetic properties and in vivo anti-tumor activity in the SJSA-1 osteosarcoma xenograft model. Continued optimization of this series led to the discovery of the sulfone-piperidinone MDM2 inhibitor, which is currently being evaluated in human clinical trials for the treatment of cancer.
About the speaker:
2001-present Scientist/Senior Scientist/Principal Scientist, Medicinal Chemistry, Amgen SF
2007-2012 Leading chemist/Group leader of oncology project: small molecule p53-MDM2 inhibitor
Major Discovery of AMG XXX, currently in the clinic trials for the treatment of cancer
Achievement Discovery of AM-XXXX, a backup clinical candidate
2002-2007 Group leader of metabolic disease project: selective 11β-HSD1 inhibitor
Major Discovery of AMG XXX, a clinical candidate
Postdoctoral Organic Chemistry, University of California, Los Angeles (UCLA), 1998-1999
Fellow Developed new methods for the total synthesis of the very cytotoxic natural
Products, tedanolide and 13-deoxytedanolide
Mentor: Professor Michael E. Jung
Ph.D. Organic Chemistry, University of Alberta, Canada, 1993-1998
Advisor: Professor Hsing-Jang Liu
M.S. Organic Chemistry, Suzhou University, China, 1987-1990
Advisor: Professor Keqian Chen
B.S. Chemistry, Suzhou University, China, 1984
PUBLISHED and FILED PATENTS (2008-present)
1. “Aryl sulfonamide compounds and uses related thereto”. U.S. Patent No: US 7,365,075 B2, 2008; U.S. Patent No: US 7,365,075 B2, 2009; U.S. Patent No: US 7,8345,047 B2, 2010.
2. “Aryl sulfones and uses related thereto”. U.S. Patent No: US 7,402,704 B2, 2008; U.S. Patent No: US 7,754,890 B2, 2010.
3. “Benzimidazole derivatives”. U.S. Patent No: US 7,635,774 B2, 2009.
4. “Benzimidazole derivatives and uses related thereto”. U.S. Patent No: US 7,605,289 B2, 2009.
5. “Diaza heterocycle amide compounds and their uses”. U.S. Patent No: US 7,524,848 B2, 2009.
6. “Diaza heterocycle sulfonamide and their uses”. U.S. Patent No: US 7,825,122 B2, 2010.
7. “Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer”. PCT No: WO 2011/153509 A1; U.S. provisional patent application was filed in June, 2011.
8. “Herocyclic compounds as MDM2 inhibitors for the treatment of cancer”. U.S. provisional patent application was filed in September, 2012.
9. “Cis-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer”. U.S. provisional patent application was filed in February, 2013.
