Abstract
Melanoma is the most serious form of skin cancer but its medication is still far from being safe and thoroughly effective. The search of novel therapeutic approaches represents therefore a health emergency to push through eagerly. In this study, we describe a novel class of dual c-Kit/Aur inhibitors, characterized by a 1,2,4-triazole core and developed by a structure-based optimization of a previously developed hit, and report the evidence of their significance as drug candidates for the treatment of melanoma. Compound 6a, merging the best inhibitory profile against the target kinases, showed anti-proliferative efficacy against the human melanoma cell lines A2058, expressing the BRAF V600D mutation, and WM266-4, expressing BRAF V600E. Significantly, it displayed also a highly synergistic profile when tested in combination with vemurafenib, thus proving its efficacy not only per se but even in a combination therapy, which is nowadays acknowledged as the cornerstone approach of the forthcoming tumour management.
Highlights
Up to four main types of melanoma may be described, differentiated by anatomic sites and clinical features, as well as by distinctive genomic alterations including amplification, deletion and mutation of selected genes encoding for particular protein kinases
A clear example of the drug design versatility of this nucleus is represented by compound DP01920, 5-(4-chlorophenyl)-3-((4-chlorophenylthio)methyl)-1H1,2,4-triazole (5, Chart 1-SI, Supplemental Information), found out through a receptor-based virtual screening campaign aimed at obtaining novel inhibitors of RET, a tyrosine kinase receptor whose gain of function is causally linked to the development of different types of thyroid cancer[28]
Obtained from a previously described hit[28] by means of a structural improvement, pursued through a rational approach facilitated by preliminary docking studies, the novel compounds are able to target two key protein kinases accountable for both pathogenesis and progression of melanoma
Summary
Up to four main types of melanoma may be described, differentiated by anatomic sites and clinical features, as well as by distinctive genomic alterations including amplification, deletion and mutation of selected genes encoding for particular protein kinases. Inducing a rapid and widespread response, which revolutionized the prognosis of patients increasing their median overall survival to two years or more, the use of these compounds is not without controversy and serious concern Their administration is limited to patients carrying the V600 BRAF mutation, malignancies characterized by a deregulation of different proteins, like c-Kit, still cannot benefit from a target therapy. The paradoxical activation of the MAPK pathway resulting from BRAF and MEK inhibition may accelerate pre-existing cancerous lesions[19,20] Most importantly, these compounds trigger resistance mechanisms in the tumour cells, due to either re-activation of the targeted pathway or de novo activation of alternative signalling routes, making patients no longer responsive to both the initial therapy and additional treatment options[21,22,23]. A clear example of the drug design versatility of this nucleus is represented by compound DP01920, 5-(4-chlorophenyl)-3-((4-chlorophenylthio)methyl)-1H1,2,4-triazole (5, Chart 1-SI, Supplemental Information), found out through a receptor-based virtual screening campaign aimed at obtaining novel inhibitors of RET, a tyrosine kinase receptor whose gain of function is causally linked to the development of different types of thyroid cancer[28]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
