Optimised arylbiamidine derivative as potent in vivo antimelanoma agent: Drug-to-target approach reveals nanomolar GSK3β inhibition

Melanoma, particularly in its metastatic form, remains highly lethal. Despite advancements in treatment, nearly half of melanoma patients experience therapeutic failure due to resistance. Consequently, the development of new antimelanoma drugs is critical for those unresponsive to current therapies. Here, we report the discovery of a potent antimelanoma scaffold and a promising inhibitor of glycogen synthase kinase 3 beta (GSK3β) through a drug-to-target approach. A phenotypic screening of arylbiamidine derivatives identified lead compound 35, N-(N-(benzo[d]thiazol-2-yl)carbamimidoyl)pyrazine-2-carboximidamide, which exhibited the highest in vitro potency against melanoma cell lines and nanomolar inhibition of oncogenic GSK3β (IC₅₀ = 73.8 nM). Moreover, compound 35 demonstrated a favourable pharmacological profile, significantly reducing tumour growth in vivo in an A375 xenograft mouse model.