Novel C-2 Aromatic Heterocycle-Substituted Triterpenoids Inhibit Hedgehog Signaling in GLI1 Overexpression Cancer Cells

The Hedgehog (Hh) signaling pathway is critical for vertebrate embryonic development, tissue homeostasis, and tumorigenesis. Its constitutive activation in various human tumors drives GLI-mediated transcription, promoting tumor progression. Following a preliminary screen of a large triterpene library that identified promising Hh inhibitors, we designed and synthesized a novel series of triterpenoid analogs with aromatic heterocyclic substituents at C-2 to enhance their Hh pathway interference.
In this study, we assessed 15 synthesized triterpenoids for VTX-27 their effects on cell proliferation and Hh pathway activity in relevant cancer cell lines. Among them, two derivatives, 11a and 11b, both featuring a furan ring at C-2, exhibited potent antiproliferative effects and induced cell death in nonsmall cell lung cancer (NSCLC) and prostate cancer cells with hyperactive Hh signaling. These compounds also significantly suppressed GLI-mediated transcription in cell-based reporter assays. Immunoblot analyses confirmed that 11a and 11b reduced endogenous GLI1 protein levels and downregulated key tumor-promoting genes, including Cyclin D1, N-Myc, and Bcl-2, in A549 and DU-145 cells.
These findings suggest that the antiproliferative effects of 11a and 11b stem from Hh pathway inhibition, positioning them as promising candidates for developing targeted therapies against Hh-dependent tumors.