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Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation.

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.

SUBMITTER: Quattrini L

PROVIDER: S-EPMC6617451 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation.

Quattrini Luca L Coviello Vito V Sartini Stefania S Di Desidero Teresa T Orlandi Paola P Ke Yi-Yu YY Liu Kai-Lun KL Hsieh Hsing-Pang HP Bocci Guido G La Motta Concettina C

Scientific reports 20190709 1

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 treatme ...[more]

PMID: 31289333

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Project description:ObjectivesBreast tumor is ranked as the most common tumor type identified among women globally with over 1.7 million cases annually, representing 11.9% of the total number of cancer cases. Approved anti-breast tumor drugs exhibit several side effects and some patients develop resistance during the early treatment stage. This study aimed to use an in-silico approach to identify and design potential therapeutic agents.MethodsRobust 3D-QSAR models were developed using quinazoline-4(3H)-one analogs as EGFR inhibitors. The best model was then selected based on statistical parameters and was subsequently used to design more potent therapeutic agents. Molecular docking simulation was executed using the data set and the designed compounds to identify lead compounds which were further screened by pharmacokinetic profiling by applying SwissADME and pkCSM software.ResultsInternal validations of the best CoMFA and CoMSIA models (R2 = 0.855 and 0.895; Q2 = 0.570 and 0.599) passed the threshold values for the establishment of a consistent QSAR model. The constructed models were further validated externally using six compounds as a test set, thus revealing a satisfactory predicted correlation coefficient (R2 pred = 0.657 and 0.681). The CoMSIA_SHE models with the best statistical parameters were further subjected to applicability domain checks and only three influentials were detected. These were then utilized to design five novel compounds with activities ranging from 5.62 to 6.03. Molecular docking studies confirmed that compounds 20 to 26, with docking scores ranging from -163.729 to -169.796, represented lead compounds with higher docking scores compared to Gefitinib (-127.495). Furthermore, the designed compounds exhibited better docking scores ranging from -171.379 to -179.138.ConclusionsPharmacological studies identified compounds 20, 24 26 and the designed compounds 2, 3, 5 as feasible drug candidates. However, these theoretical findings should now be validated experimentally.

Dataset Information

Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation.

Publications

Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation.

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