ABSTRACT. Full Project 1. PI: Dr. Yong Wu Triple-negative breast cancer (TNBC) is a heterogeneous subtype comprising 10-15% of breast cancer incidences. It's notorious for poor outcomes, recurrence, chemoresistance, and disproportionately affecting younger women, African Americans (AAs), and those carrying hereditary mutations. Treatments are chemotherapy-based, with a need for improved categorization methods and targeted therapies. Leukemia, distinguished by excessive production of abnormal leukocytes, leans on chemotherapy as the primary treatment. However, chemotherapy is ineffective in certain leukemia types, underscoring the need for personalized approaches. Acute myeloid leukemia (AML), in particular, exhibits unbalanced health impacts among minority ethnicities, predominantly Black and Hispanic patients who face lower survival rates. Despite the availability of numerous drugs on the market and in clinical trials, notable gaps persist, highlighting the urgent need for targeted, personalized treatments and therapies to address significant health disparities in these diseases. Monocarboxylate transporter 4 (MCT4) links to TNBC and leukemia development and prognosis, and its overexpression is associated with poor prognosis in TNBC and AML. Although inhibiting MCT4 may suppress TNBC/leukemia cell proliferation and increase chemosensitivity, further research is needed to understand the role of MCT4 and potential treatment strategies in these diseases. Considering the shared MCT4 overexpression, common chemoresistance, and health disparities in both TNBC and AML, this project concurrently studies these two diseases to utilize resources and enhance broader therapeutic insights efficiently. Given that existing MCT4 inhibitors, like AZD0095, phloretin, and α-CN-4-OH-cinnamate, exhibit lackluster efficacy and specificity, we need more potent/selective inhibitors. Our newly developed MCT4- targeting small molecule inhibitor, CB-2, has demonstrated potent anticancer activity in preclinical studies. Besides, CB-2 enhances the chemo-sensitivity, offering combination therapy prospects. However, the notable instability of CB-2 presents a substantial challenge to its potential clinical application; there is also a need for further enhancement of the anticancer efficacy of CB-2. Here, we propose to test whether an improved MCT4 inhibitor, CB-2O2, has more potent anticancer activity and stability. Our preliminary studies show that CB-2O2 has superior stability and anticancer activity and increases chemotherapy sensitivity among TNBC and AML cells. Thus, we will evaluate if this compound and newly designed backup analogs can inhibit TNBC and leukemia more completely and increase their sensitivity to chemotherapy by pursuing three Aims.