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IAP Antagonists for lung cancer treatment

Institution: The Burnham Institute for Medical Research
Investigator(s): John Reed, M.D., Ph.D.
Award Cycle: 2004 (Cycle 13) Grant #: 13RT-0130 Award: $727,658
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
BACKGROUND: Lung cancer is caused in part by a failure of lung cells to die in accordance with the natural lifespan regulation of cells. Normally, in the lung and other self-renewing tissues, billions of cells are produced daily, offset by a commensurate amount of cell death. This cell suicide mechanism becomes defective in cancers, contributing to malignant cell accumulation and making tumor cells difficult to kill by chemotherapy and radiation. Among the endogenous proteins that block cell death in cancers in XIAP, which is over-produced in many lung cancers. Our mission is to devise drugs that inhibit XIAP, thus restoring the normal cell suicide mechanism in advanced lung cancer.

ACCOMPLISHMENTS: We have produced synthetic chemicals that bind XIAP and that negate its ability to block tumor cell death. Multiple variants of the chemicals were produced to explore the structural features optimal for suppression of XIAP. Several equally effective, optimized chemicals have been generated and shown to kill cancer cells in laboratory experiments.

FUTURE PLANS: Using the optimized chemical inhibitors of XIAP, we plan to further characterize the mechanism by which they kill cancer cells, determine the safety and pharmacological properties of these chemicals when injected into animals, and test their ability to inhibit tumor growth in animals. These studies will lay a foundation for eventual clinical trials.

793 Structure activity relation study of small-molecule antagonists of apoptosis suppressor XIAP
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Welsh, K, Pinilla, C Nefzi, A., Ostresh, J.M., Pellecchia, M., Houghten R.A. Reed, J.C. ABS
Yr: 2006 Vol: 47 Nbr: Abs: Pg: 793