Electrochemical Synthesis of New Isoxazoles and Triazoles Tethered with Thiouracil Base as Inhibitors of Histone Deacetylases in Human Breast Cancer Cells.

Article

Author: Basappa, Shreeja ; Mohan, Arunkumar ; Krishnamurthy, Niranjan Pattehalli ; Pandey, Vijay ; Ravish, Akshay ; Vishwanath, Divakar ; Gaonkar, Santosh L ; Xi, Zhang ; Basappa, Basappa ; Lobie, Peter E

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC₅₀ value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.

26 Sep 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models

Q1 · MEDICINE

Article

Author: Shen, Sida ; Zimprich, Chad A. ; Villagra, Alejandro ; Ustinova, Kseniya ; Tavares, Mauricio T. ; Pavlicek, Jiri ; Knox, Tessa ; Zhang, Guiping ; Noonepalle, Satish ; Hadley, Melissa ; Bařinka, Cyril ; Kozikowski, Alan P. ; Robers, Matthew B.

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Discovery	US	University of Illinois	26 Sep 2019
Melanoma	Discovery	US	Promega Corp.	26 Sep 2019
Melanoma	Discovery	US	StarWise Therapeutics LLC	26 Sep 2019

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