Rational design, synthesis, and bioassay of small molecules for inhibition of the mTOR signaling pathway

MEDI 329

Jun Yong Choi, jychoi@ic.sunysb.edu1, Elzbieta S. Selinger, elselinger@notes.cc.sunysb.edu2, Lisa M. Ballou, lballou@notes.cc.sunysb.edu2, Richard Z. Lin, rzlin@notes.cc.sunysb.edu2, and Dale G. Drueckhammer, ddrueckhamme@notes.cc.sunysb.edu1. (1) Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, (2) Department of medicine, Stony Brook University, Stony Brook, NY 11794
The mammalian target of rapamycin (mTOR) is an attractive target for cancer treatment, as the signaling mediated by mTOR is hyperactivated in many human cancers. mTOR forms two multiprotein complexes (mTORC1 and mTORC2) that have different activities. It has been shown that rapamycin only inhibits the mTORC1 complex, with mTORC2 being rapamycin-insensitive. Small molecules that bind directly to the mTOR catalytic site and block the activities of both mTOR complexes are expected to have broader anti-cancer activity than the rapamycin. Homology modeling was performed to identify active site differences between mTOR and the homologous phosphoinositide-3-kinases (PI3Ks) and DNA-dependent protein kinase. The lead compounds have been further modified based on these modeling results. The designed compounds have been synthesized and tested against mTOR and PI3Ks. Inhibitors having increased potency and selectivity against mTOR have been obtained, supporting the modeling approach and providing improved compounds for further development of potential anti-cancer agents.
 

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