Mechanisms of Apoptosis Dysregulation in AMI (John C. Reed, MD, PhD) The successful eradication of leukemia cells depends largely on induction of apoptosis. Defects in apoptosis pathways, therefore, can contribute to chemoresistance and treatment failures. The goal of this renewal application is to build on progress made during the prior funding period, exploring novel strategies for over-coming roadblocks to apoptosis in Acute Myelogenous Leukemia (AML) using chemical inhibitors of anti- apoptotic proteins. Specifically, we proposed to: (1) Explore the activity of chemical inhibitors of antiapoptotic Bcl-2-family proteins against cultured AML cells, contrasting BH3 mimics with TR3 mimics;(2) Determine the pro-apoptotic activity of chemical inhibitors of lAP-family proteins against cultured AML cells, contrasting SMAC mimics with non-SMAC mimics;and (3) Perform siRNA-based screens of the human kinome to identify kinase targets suitable for synergistic induction of apoptosis in combination with Bcl-2 inhibitors or IAP inhibitors. Chemical antagonists of anti-apoptotic proteins will be studied in combination with agents and treatment strategies under evaluation by other Project members, thus identifying opportunities for synergistic elimination of AML cells. Altogether, these studies will contribute to an eventual optimized, apoptosis-based strategy for treatment of AML, providing a foundation of preclinical data for design of human clinical trials.