Preclinical antitumor activity of BMS-690514, a panHER/VEGFR2 kinase inhibitor

MEDI 17

Ashvinikumar V. Gavai, ashvinikumar.gavai@bms.com1, Ping Chen1, Derek Norris, derek.norris@bms.com1, Brian E. Fink1, Harold Mastalerz, harold.mastalerz@bms.com1, Yufen Zhao1, Wen-Ching Han1, Guifen Zhang1, Walter Johnson1, Edward Ruediger2, Pierre Dextraze2, Jean-Paul Daris1, Soong-Hoon Kim1, Kenneth Leavitt1, Kyoung Kim, kyoung.kim@bms.com2, Songfeng Lu1, Peter Zheng1, Arvind Mathur3, Dinesh Vyas1, John S. Tokarski4, Chiang Yu5, Simone Oppenheimer5, Hongjian Zhang6, Francis Lee5, Tai W. Wong5, and Gregory D. Vite, gregory.vite@bms.com1. (1) Discovery Chemistry, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, (2) Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Industrial Boulevard, Candiac, QC J5R 1J1, Canada, (3) Discovery Chemistry, Bristol-Myers Squibb, P. O. Box 4000, Princeton, NJ 08543-5400, (4) Structural Biology and Modeling, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543, (5) Oncology Drug Discovery, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, (6) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000
HER1(EGFR) and HER2 (ErbB2) are cell-surface growth factor receptor tyrosine kinases that are known to play a crucial role as signal transducers and have been implicated in a number of cancers. Frequent co-expression of HER1 and HER2 in a variety of tumor types and their capacity to form heterodimers with other members of the EGFR family provide a strong rationale for simultaneous targeting of the two receptors. Tumor angiogenesis is regulated by VEGF, a mitogenic growth factor that signals through the VEGFR2 kinase on endothelial cells. This presentation will summarize efforts at Bristol-Myers Squibb on a series of pyrrolotriazine-based HER1/HER2 and VEGFR2 kinase inhibitors that culminated in identification of BMS-690514 as the clinical candidate. BMS-690514 demonstrated antiproliferative activity against HER1 and/or HER2-overexpressing cell lines and inhibited the proliferation of VEGF-stimulated human umbilical vein endothelial cells. Structure-activity relationships will be described along with in vivo evaluation of the clinical candidate in relevant tumor xenograft models. BMS-690514 is currently in Phase I clinical trials for the treatment of cancer.
 

First Time Disclosure of Clinical Candidates
1:30 PM-5:30 PM, Sunday, March 25, 2007 McCormick Place Lakeside -- Room E353 A/B, Level 3, Oral

Division of Medicinal Chemistry

The 233rd ACS National Meeting, Chicago, IL, March 25-29, 2007