Researchers at the University of Pittsburgh and the University of Illinois have developed a first-in-class small molecule inhibitor (STL001) that selectively targets the transcription factor FOXM1, a key driver of tumor proliferation, chemoresistance, and poor clinical outcomes. STL001 represents a novel therapeutic strategy for sensitizing cancer cells to chemotherapy by promoting FOXM1 degradation through nuclear relocalization and autophagy—an approach not previously employed in FOXM1-targeting drug discovery.
Description
FOXM1 is overexpressed in a wide range of human cancers and plays a central role in cell cycle regulation, DNA damage repair, and resistance to chemotherapy. High nuclear FOXM1 levels have been associated with inferior survival in patients with acute myeloid leukemia (AML) and contribute to poor responses to chemotherapeutics such as 5-fluorouracil, platinum agents, and taxanes.
STL001 is an optimized analog of an earlier hit (STL427944) identified via network-based transcriptomic screening. It acts by inducing nuclear export and autophagy-mediated degradation of FOXM1 protein, resulting in suppression of FOXM1-dependent signaling pathways. In vitro data confirm STL001’s ability to sensitize diverse cancer cell lines to chemotherapy, including AML, triple-negative breast cancer, colorectal, ovarian, and prostate cancers. Transcriptome profiling and gene set enrichment analysis further support the specificity and mechanistic relevance of FOXM1 inhibition.
Applications
• Acute myeloid leukemia (AML)
• Triple-Negative and Tamoxifen-Resistant Breast Cancer
• Ovarian, Colorectal, and Prostate cancer
• Other solid tumors with FOXM1 overexpression or chemoresistance
Advantages
• Novel Mechanism: First compound class to degrade FOXM1 through cytoplasmic relocalization and autophagy.
• Therapeutic Synergy: Sensitizes cancer cells to a wide range of standard chemotherapies.
• High Specificity: RNA-seq and knockdown studies confirm selective targeting of FOXM1-driven pathways.
• Broad Impact: Applicable to multiple cancers where FOXM1 drives resistance and poor prognosis.
• First-in-Class Potential: No other small molecules approved or clinically advanced for FOXM1 inhibition.
Invention Readiness
In vitro studies across multiple human cancer cell lines have demonstrated FOXM1 suppression at concentrations as low as 1 µM, with clear synergistic effects when combined with standard chemotherapeutic agents. Transcriptomic analyses confirm high specificity toward FOXM1-regulated networks.
IP Status
https://patents.google.com/patent/WO2024137979A2
