Abstract Novel HIF1? Inhibitors for the Treatment of Breast Cancer HIF1? (hypoxia inducible factors) is overexpressed in many types of cancers such as breast cancer. Currently there is no FDA approved drug that specifically target HIF-1?. Existing HIF-1? inhibitors suffered from low selectivity and high toxicity. We have discovered novel sets of small molecules (CJ-3-60 analogs) based on a widely used HIF-1? inhibitor, YC-1. Preliminary data showed that CJ-3-60 is significantly more potent for HIF-1? inhibition and less toxic than YC-1. The proposed research to develop new CJ-3-60 analogs is highly innovative: First, the proposed new analogs are expected to have high selectivity against breast cancer cells overexpressing HIF1?; Second, the proposed structural modifications will generate highly active HIF-1? inhibitors with variable micropharmacokinetic properties that will allow for optimal penetration to tumor hypoxic regions which is another major limitation for existing HIF-1? inhibitors. The proposed study will provide proof-of-concept for a future R01/SC1 application in which we will perform in-depth mechanistic studies, comprehensive in vivo efficacy and toxicity studies.