Abstract It is a Fast-Track R43/R44 application containing both Phase I and Phase II. We have already demonstrated the feasibility of a SATB2 inhibitor (patented molecule), which is effective in vitro and in vivo. In US, hepatocellular Carcinoma (HCC) incidence has tripled over the past two decades and is expected to become the third leading cause of cancer deaths by 2030. African Americans (AA) have been shown to exhibit a higher incidence of HCC and experience lower survival compared with Caucasian Americans (CA). The disease has disproportionately affected minority and disadvantaged populations. Health disparities arise from the conditions in which people are born, grow, live, and work. There is increasing recognition that adverse environment and unfavorable living conditions, economic status, stress, and genetic factors affect an individual’s health through oncogenic pathways leading to HCC development. Unfortunately, these factors/pathways are involved in the initiation and progression of HCC and therefore are responsible for racial disparities in HCC incidence and mortality. Special AT-rich binding protein 2 (SATB2) is a nuclear matrix protein that acts as a key regulator of gene expression and chromatin remodeling. SATB2 modulates the expression of genes, which regulates pluripotency and self-renewal of cancer stem cells (CSCs). Higher expression of SATB2 in HCC from AA, compared to CA patients, was positively associated with greater cell growth and metastasis. This suggests that SATB2 expression or function can be exploited for eliminating HCC racial disparities in AA. There are no FDA-approved small organic molecule-based SATB2 inhibitors in the market. The goal of this project is to develop chemotherapy in which the newly discovered SATB2 inhibitor inhibits higher HCC growth in AA, compared to CA, using clinically relevant cancer cell lines, and patient- derived tumor (PDX) model established from HCC tissues derived from AA and CA patients, resulting in eliminating HCC disparities in AA. We hypothesize that differential expression of SATB2 in HCC tissues of AA determines more aggressive phenotypes than those in CA, and SATB2 inhibitor suppresses higher HCC tumor growth in AA compared to CA, resulting in eliminating HCC disparities in AA. Aim 1. To use artificial intelligence (AI) techniques to identify potent SATB2 inhibitors (Phase I). Aim 2. To examine the biological effects of SATB2 inhibitors using HCC samples isolated from AA and CA patients in vitro (Phase I). Aim 3. To examine the maximum tolerable dose and toxicity of the SATB2 inhibitor in mice (Phase II). Aim 4. To examine whether SATB2 inhibitor suppresses higher growth of HCC tumors from AA than those from CA, resulting in the elimination of racial disparities (Phase II). Artificial intelligence (AI) techniques will be performed to identify non-toxic and drug-like selective SATB2 inhibitors. Binding residues of SATB2 which interact with SATB2 inhibitor (small organic molecul...