Discovery of ß-sulfonamide piperidine hydroxamates as potent and selective HER-2 sheddase inhibitors

MEDI 365

David M. Burns, dburns@incyte.com1, Chunhong He1, Yanlong Li1, Peggy Scherle1, Maryanne Covington2, Max Pan1, Richard Wynn1, Sharon Turner1, Jordan S. Fridman1, Steve Friedman1, Brian Metcalf1, and Wenqing Yao, WYao@incyte.com1. (1) Medicinal Chemistry, Incyte Corporation, Experimental Station-E336/212, Route 141 and Henry Clay Road, Wilmington, DE 19880, (2) Bristol-Myers Squibb Company
The human epidermal growth factor receptor-2 (HER-2) is a tyrosine kinase receptor that is activated upon homo-and heterodimerization with another member of the HER family or by proteolytic cleavage (shedding) of the extracellular domain (ECD). Overexpression of the oncogene HER-2/neu has been associated with aggressive pathogenesis, poor prognosis, and decreased responsiveness to conventional chemotherapeutic and hormonal treatment regimes in non-small cell lung cancer, ovarian cancer, and breast cancer patients. In addition, elevated plasma levels of HER-2 ECD have been associated with increased metastatic potential and a decrease in disease-free and overall survival in patients with breast cancer. Therefore, inhibition of the protease responsible for HER-2 ECD shedding, which has recently been identified as ADAM-10, may be therapeutically desirable for treating cancer patients that overexpress HER-2. Several ß-sulfonamide piperidine hydroxamates were identified to be potent inhibitors of HER-2 sheddase with excellent selectivity over other matrix metalloproteases (MMPs).

 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007