Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.
Department of Biochemistry and Molecular Medicine , The George Washington University , Washington, District of Columbia 20052 , United States.
J Med Chem. 2019 Sep 26;62(18):8557-8577. doi: 10.1021/acs.jmedchem.9b00946. Epub 2019 Sep 4.
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 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.
异恶唑是一种五元杂环，广泛应用于药物研发领域。在这里，我们报告了 SS-208 的设计、合成、结构和生物学特性，它是一种新型的 HDAC6 选择性抑制剂，含有异恶唑-3-羟肟酸部分作为锌结合基团和疏水连接子。HDAC6/SS-208 复合物的晶体结构揭示了活性位点锌离子的双齿配位，与基于苯羟肟酸的抑制剂的 HDAC6 复合物中观察到的优选的单齿配位不同。虽然 SS-208 对体外培养的小鼠 SM1 黑色素瘤细胞的活力几乎没有影响，但它在小鼠 SM1 同源性黑色素瘤小鼠模型中显著抑制了体内肿瘤生长。这些发现表明，SS-208 的抗肿瘤活性主要是通过免疫相关的抗肿瘤活性介导的，这表现在肿瘤微环境中 CD8+和 NK+T 细胞的浸润增加和 M1 和 M2 巨噬细胞的比例增强。
