Acute myeloid leukemia (AML) is the most common acute leukemia in adults, and the 5-year survival remains dismal at only 26% in adults. Disease that relapses after therapy or does not respond to therapy at all remains a major challenge. Chemotherapy drugs used for AML have remained largely unchanged since the 1970s, and current treatment approaches fail to cure most patients. Thus, identification of novel vulnerabilities to enable new therapeutic approaches in AML would have major clinical impact. We discovered a series of drug-like molecules that work through a novel mechanism to kill leukemia cells. These compounds bind a protein named RPS23, which is a component of the machinery that ce...

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Acute myeloid leukemia (AML) is the most common acute leukemia in adults, and the 5-year survival remains dismal at only 26% in adults. Disease that relapses after therapy or does not respond to therapy at all remains a major challenge. Chemotherapy drugs used for AML have remained largely unchanged since the 1970s, and current treatment approaches fail to cure most patients. Thus, identification of novel vulnerabilities to enable new therapeutic approaches in AML would have major clinical impact. We discovered a series of drug-like molecules that work through a novel mechanism to kill leukemia cells. These compounds bind a protein named RPS23, which is a component of the machinery that cells use to make proteins. In doing so, they turn on a stress response pathway. Leukemia cells are acutely sensitive to the stress response program, and its activation kills leukemia cells but not other cell types. This application seeks to validate RPS23 as a leukemia drug target and identify viable drug leads. Initial work identified potent and stable compounds. Proof-of-concept studies showed that a lead compound could significantly prolong overall survival in an aggressive mouse model of AML with minimal toxicity. We propose to synthesize optimized drug leads for further study. As part of these studies, we will define the dose of drug needed to kill leukemia cells while being well tolerated by patients by carefully monitoring effects on normal blood cells. We will also evaluate the range of leukemias and lymphomas that are susceptible to treatment with these drugs using patient derived xenografts. Our research team includes expertise in medicinal chemistry, leukemia and biochemistry. The basic scientists and physician scientists on the research team will define the optimal dosing protocol for drugs that bind to RPS23, discover improved versions of these drugs, and identify the cancer subtypes that could most benefit from this new treatment strategy.

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