Discovery of SATB2 Inhibitors for Pancreatic Cancer

Abstract Pancreatic cancer is a slow-growing disease with a 5-year survival rate of approximately 9%. It is the fourth leading cause of cancer-related deaths in the US. Currently used pancreatic cancer drugs are not very effective and exhibit severe side effects. Patients develop drug resistance and ultimately cancer relapse due to

the generation of cancer stem cells (CSCs), which play significant roles in tumor initiation, promotion, metastasis, and chemotherapy failure. Thus, there is an urgent need to develop new non-toxic drugs to improve pancreatic cancer patients’ outcomes. 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 is highly expressed in pancreatic cancer cells and CSCs, but not in human pancreatic normal ductal epithelial cells. Nanog, a transcription factor, is highly expressed in mouse and human pluripotent stem cells. Nanog overexpression

has been detected in cancer and CSCs, and is correlated with cell proliferation, tumor recurrence, clonogenic development, tumorigenicity, invasiveness, and resistance to chemotherapy. STAB2 plays a significant role in the pluripotency and self-renewal of stem cells and inhibits pancreatic cancer cell growth. SATB2 regulates

the expression of pluripotency maintaining and self-renewal factors (Oct-4, Sox-2, Nanog, cMyc, and KLF4). Furthermore, overexpression of the SATB2 gene induces malignant transformation, and inhibition of SATB2 expression by shRNA inhibits pancreatic cancer growth; suggesting the oncogenic role of SATB2 in pancreatic

cancer. Unfortunately, there are no small organic molecule-based FDA-approved SATB2 inhibitors in the market. The main objective of this application is to identify and validate SATB2 inhibitors for the treatment of pancreatic cancer using molecular docking, molecular dynamics simulations, and in vitro cell culture

approaches. Our hypothesis is that the SATB2 inhibitor suppresses pancreatic cancer growth by inhibiting Nanog expression. Aim 1. To perform molecular screening and docking studies to find selective SATB2 inhibitors. Aim 2. To examine the molecular mechanisms by which SATB2 inhibitors suppress human

pancreatic cancer growth in vitro. Molecular docking studies, molecular dynamics simulations, and QikProp analysis will be performed to identify non-toxic and drug-like selective SATB2 inhibitors. Biding residues of SATB2 which interact with specific compounds (SATB2 inhibitors, small organic molecules) will also be

identified. The effects of SATB2 inhibitors on binding to SATB2 proteins, Nanog transcription, cell viability, apoptosis, spheroid and colony formation, and epithelial-mesenchymal transition (EMT) will be examined. The effects of SATB2 inhibitors on the expression of pluripotency and self-renewal genes (Oct-4, Sox-2, KLF-4,

cMyc, and Nanog), and stem cell markers (CD24, CD44, and CD133) will be measured by qRT-PCR and/or western blot analysis. SATB2 binding partners/targets will be identified by Chromatin Immunoprecipitation Sequencing (ChIP-seq). In conclusion, our studies are highly innovative and offer significant preclinical

benefits by developing non-toxic SATB2 inhibitors for the treatment of pancreatic cancer.