Targeting scaffold/matrix associated regions in pancreatic ductal adenocarcinoma: A novel carbazole-derived therapeutic

Pancreatic cancer is the tenth most common cancer in the United States and is projected to become the second leading cause of cancer-related death by 2030. Most cases arise in exocrine cells and are driven by genetic mutations, such as KRAS and CDKN2A , as well as modifiable risk factors, including alcohol use, chronic pancreatitis, and obesity. The aggressive nature of pancreatic ductal adenocarcinoma (PDAC), coupled with its complex tumor microenvironment, leads to late-stage diagnoses and a five-year survival rate of 13%. Despite advances in treatment, which include surgical resection, radiotherapy, and chemotherapeutic regimens like gemcitabine and FOLFIRINOX, therapy-related toxicity and chemotherapy resistance remain significant barriers to improved outcomes. One promising therapeutic approach involves exploiting vulnerabilities in the DNA damage response (DDR) pathways unique to cancer cells. While cancer cells rely on an aberrant DDR to sustain unchecked replication, their increased mutational burden renders them particularly susceptible to DNA-targeting therapies. However, existing DNA-targeting treatments are limited by off-target effects, resulting in toxicity and the emergence of resistance. This underscores the need for novel, selective drugs capable of targeting DNA processes specific to cancer cells. We report on a novel carbazole-derived compound that represents a significant advancement in PDAC therapy. Carbazole, a nitrogen-containing heterocyclic molecule, serves as a pharmacophore in therapeutics with diverse applications, including antitumor, antiviral, and anti-inflammatory agents. Our compound demonstrates potent inhibition of PDAC growth and metastasis in both in vitro and in vivo models while sparing normal cells. Its mechanism of action involves selective targeting of Scaffold/Matrix Associated Regions (S/MARs), which play critical roles in chromatin organization and gene expression regulation. By disrupting S/MARs and their associated binding proteins, our compound downregulates essential genes involved in replication and DNA repair, including CDK4 , MCMs , GINS , and CDC6 . These findings suggest that our compound offers a unique therapeutic mechanism with high specificity and minimal toxicity. Furthermore, its potential to complement existing treatments and advance toward Investigational New Drug (IND) approval positions it as a promising candidate for PDAC therapy.