Design and synthesis of c-met kinase inhibitors based on an in silico screen-derived lead

MEDI 361

Sung-Eun Kim, kims@ncifcrf.gov1, Zhen-Dan Shi, shizh@nhlbi.nih.gov1, Megan Peach, mpeach@helix.nih.gov1, Alessio Giubellino, giubella@mail.nih.gov2, Marc C Nicklaus, mn1@helix.nih.gov1, Donald Bottaro, bottarod@mail.nih.gov2, and Terrence R Burke Jr., tburke@helix.nih.gov1. (1) Laboratory of Medicinal Chemistry, CCR, NCI, NIH, 376/217 NCI, Frederick, MD 21702, (2) Urology Oncology Branch, CCR, NCI, NIH, Bldg. 10, CRC, Rm, 1-5848, 10 Center Dr. MSC 1107, Bethesda, MD 20892
c-Met is a prototypic member of a subfamily of receptor tyrosine kinases (RTKs), which regulates a variety of cellular functions dealing with cellular growth and morphogenesis. Abnormal function of c-Met has been detected in a number of cancers, among which are breast, lung, melanoma, colorectal, prostate, ovarian and pancreatic cancers. Recently, several c-Met RTK inhibitors, including PHA665752, SU11274, SU11271 and PF-02341066 have been examined as potential new anticancer therapeutics. Using an in silico screen carried out on a database of commercially-available compounds, several potential c-Met RTK inhibitors were identified and evaluated for their ability to inhibit the c-Met RTK in whole cell systems. These compounds were hypothesized to bind in the ATP binding cleft of c-Met though interaction with a lipophylic area, while serving as a hydrogen bond acceptor with a key tyrosyl residue. Additionally, pi-stacking with the aromatic ring of a tyrosyl residue was also envisioned. Structural exploration of one of these in silico-derived c-Met RTK inhibitors will be presented.
 

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

Division of Medicinal Chemistry

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