New TRPM8 Amino Acid-Based Antagonists Induce Antiproliferative Effect on 2D and 3D Melanoma and Prostate Cancer Models.

The pharmacological potential of TRPM8 modulators ranges from neuropathic pain to tumor treatment, as this channel is involved in intracellular calcium homeostasis. We acquired considerable expertise in developing TRPM8 antagonists, which were pharmacologically characterized for their analgesic properties and their antiproliferative activity in prostate cancer. Based on the structural knowledge gained in this field, we designed and synthesized a new series of TRPM8 blockers which was validated by calcium fluorimetry and electrophysiology experiments. In silico studies helped to rationalize compounds activity, improving the structural insights about this target. The most promising TRPM8 antagonists were evaluated in melanoma and prostate 2D and 3D cancer models. From this investigation, three compounds, 7, 29, and 34, emerged as the most promising candidates; thus, they were further analyzed for their druggability by in vitro pharmacokinetic experiments. This study revealed compound 7 as the most chemically and metabolically stable derivative, highlighting its suitability for further pharmacological evaluation.