FOXM1 Inhibitors as Potential Diagnostic Agents: First Generation of a PET Probe Targeting FOXM1 To Detect Triple‐Negative Breast Cancer in vitro and in vivo

• Published in: ChemMedChem 2021-12, Vol.16 (24), p.3720-3729
• Main Authors: Pérez, David J., Amirhossein Tabatabaei Dakhili, Seyed, Bergman, Cody, Dufour, Jennifer, Wuest, Melinda, Juengling, Freimut D., Wuest, Frank, Velázquez‐Martínez, Carlos A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast cancer; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemoresistance; Deoxyribonucleic acid; Diagnostic agents; DNA; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Fluorination; Fluorine isotopes; Forkhead Box Protein M1 - antagonists & inhibitors; Forkhead Box Protein M1 - metabolism; Gene expression; Humans; Inhibitors; Mammary Neoplasms, Experimental - diagnosis; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Metastases; Mice; Molecular Structure; Positron emission; Positron emission tomography; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Radioactive tracers; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tomography; transcription factors; Triple Negative Breast Neoplasms - diagnosis; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Tumors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100279

The FOXM1 protein controls the expression of essential genes related to cancer cell cycle progression, metastasis, and chemoresistance. We hypothesize that FOXM1 inhibitors could represent a novel approach to develop 18F‐based radiotracers for Positron Emission Tomography (PET). Therefore, in this report we describe the first attempt to use 18F‐labeled FOXM1 inhibitors to detect triple‐negative breast cancer (TNBC). Briefly, we replaced the original amide group in the parent drug FDI‐6 for a ketone group in the novel AF‐FDI molecule, to carry out an aromatic nucleophilic (18F)‐fluorination. AF‐FDI dissociated the FOXM1‐DNA complex, decreased FOXM1 levels, and inhibited cell proliferation in a TNBC cell line (MDA‐MB‐231). [18F]AF‐FDI was internalized in MDA‐MB‐231 cells. Cell uptake inhibition experiments showed that AF‐FDI and FDI‐6 significantly decreased the maximum uptake of [18F]AF‐FDI, suggesting specificity towards FOXM1. [18F]AF‐FDI reached a tumor uptake of SUV=0.31 in MDA‐MB‐231 tumor‐bearing mice and was metabolically stable 60 min post‐injection. These results provide preliminary evidence supporting the potential role of FOXM1 to develop PET radiotracers. Targeting FOXM1 for triple‐negative breast cancer detection: We report preliminary results to validate FOXM1 transcription factor as a target for triple‐negative breast cancer detection, using a 1st generation 18F‐radiolabeled FOXM1 inhibitor as a PET tracer in vitro and in vivo.