作者: Cuffaro, Doretta ; Orlandini, Elisabetta ; Fabbi, Marina ; Nuti, Elisa ; Ortore, Gabriella ; Campelli, Francesco ; Ciccone, Lidia ; Nencetti, Susanna ; Gangemi, Rosaria ; Ballante, Flavio ; Rossello, Armando ; Carbotti, Grazia ; Banti, Irene ; Marshall, Garland R.

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.

2020-09-01·Journal of Molecular Graphics and Modelling4区 · 生物学

Identification of potential indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors by an FBG-based 3D QSAR pharmacophore model

4区 · 生物学

Article

作者: Zhang, Lu ; Chen, Xiaoguang ; Xiao, Zhiyan ; Lai, Fangfang

As a rate-limiting enzyme in the major pathway of l-tryptophan catabolism, indoleamine 2, 3-dioxygenase 1 (IDO1) has been regarded as a potential target for the treatment of a variety of diseases. To identify the key molecular features and extend the structural variety of IDO1 inhibitors, a ferrous binding group (FBG)-based 3D-QSAR pharmacophore model was constructed, validated and used for virtual screening herein. The Specs database was initially filtered based on drug-like rules, and was subsequently screened by the pharmacophore model. Molecular docking simulations and similarity analysis were then followed to prioritize twenty compounds for biological tests. Among them, compound VS-13 exhibited moderate inhibitory activity against IDO1, and could be subjected to further structure-activity relationship studies and structural optimization.

100 项与 VS-013 相关的药物交易

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