BLM as a potential therapeutic target in cutaneous malignant melanoma.

Skin cutaneous melanoma (SKCM) is highly aggressive, has a poor prognosis, and readily develops drug resistance. Therefore, elucidating new mechanisms underlying the development and progression of cutaneous malignant melanoma, identifying specific new targets, and developing effective therapeutics based on these targets has become a current research priority. This study analyzed clinical tissue samples from SKCM patients, revealing that BLM DNA helicase (BLM) is highly expressed in SKCM tissues but minimally expressed in pigmented nevus tissues. Furthermore, BLM expression correlates with patient survival, highlighting its significant role in melanoma development. These findings position BLM as a promising target for anti-melanoma therapy. Building on this, a trifluoromethylpyrimidine derivative (FMD-108) targeting BLM was identified from a chemical library of natural products and derivatives developed by our team. In vitro and in vivo experiments demonstrated that FMD-108 notably inhibited cancer cell growth and metastasis, while significantly modulating the expression of DNA damage markers (γ-H2AX, p-CHK1, p-CHK2), apoptosis-related proteins (Bcl-2, Bax), and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, Vimentin). These results suggest that FMD-108 effectively suppresses melanoma cell proliferation and metastasis by inducing apoptosis, arresting the cell cycle at the G1 phase, and inducing DNA damage. These findings suggest that BLM may serve as a potential target in cutaneous malignant melanoma, providing a prospective strategy for clinical anti-melanoma drug development.