FT895 is an effective selective inhibitor of histone deacetylase 11 (HDAC11), with an IC50 value of 3nM [1]. HDAC11 is a novel and unique member of the histone deacetylase family, which is highly expressed in specific tissues and certain cancer cell lines [2]. HDAC11 possesses both histone and non-histone[3] deacetylase activities and can participate in cellular activities such as chromatin remodeling and metabolic signaling pathways by regulating the acetylation state of the cell[3]. As a selective inhibitor of HDAC11, FT895 has demonstrated excellent cellular activity and pharmacokinetic properties[4], making FT895 an effective tool for studying the biological mechanisms of HDAC11. Additionally, FT895 holds promising applications in the treatment of cancer and inflammatory diseases.
In vitro, treatment with FT895 (10μM) for 24 hours resulted in a significant reduction of migration ability in A549 and H1650 cells[5]. Treatment with FT895 (10μM) for 1 hour resulted in a significant improvement of bactericidal efficiency in BMDM (Bone Marrow Derived Macrophage) cells[6].
In vivo, intraperitoneal injection of FT895 (10mg/kg/day) for 5 days in C57BL/6J mice promoted the expression of the mitochondrial inner membrane transporter UCP1 (Uncoupling protein 1) in adipose tissue through the inhibition of HDAC11, ultimately resulting in an increase in core body temperature in mice [7]. Intraperitoneal injection of FT895 (50mg/kg/day) for 7 days in C57BL/6 mice led to the inhibition of HDAC11 activity, which upregulated the expression of the anti-inflammatory cytokine IL-10 (Interleukin-10), thereby promoting anti-inflammatory responses and reducing the replication of enteric virus EV71 in the mice[8].
References:
[1] Huang, P.-Y., et al., FT895 Impairs Mitochondrial Function in Malignant Peripheral Nerve Sheath Tumor Cells. International Journal of Molecular Sciences, 2023. 25(1).
[2] Lin Gao, M.A.C., Fred Asselbergs, Peter Atadja, Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family. Journal of Biological Chemistry, 2002. 277(28): p. 25748-25755.
[3] Joshi, P., et al., The functional interactome landscape of the human histone deacetylase family. Molecular Systems Biology, 2013. 9(1): p. 672.
[4] Matthew W. Martin, J.Y.L., David R. Lancia, Pui Yee Ng, Bingsong Han, Jennifer R. Thomason, Maureen S. Lynes, C. Gary Marshall, Chiara Conti, Alan Collis, Monica Alvarez Morales, Kshama Doshi, Aleksandra Rudnitskaya, Lili Yao, Xiaozhang Zheng, Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11. Bioorganic & Medicinal Chemistry Letters, 2018. 28(12): p. 2143-2147.
[5] Bora-Singhal, N.e.a., Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2. Scientific reports, 2020. 10,1 4722.
[6] Wu, H.e.a., HDAC11 negatively regulates antifungal immunity by inhibiting Nos2 expression via binding with transcriptional repressor STAT3. Redox biology, 2022. 56 (2022): 102461.
[7] Robinson EL, B.R., Major JL, Bergman BC, Matsuda JL, McKinsey TA, HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance. J Clin Invest, 2023.
[8] Xie, H.e.a., Targeting HDAC11 activity by FT895 restricts EV71 replication. Virus research, 2023. vol. 330 (2023): 199108.
FT895是组蛋白脱乙酰酶11（Histone Deacetylase 11，HDAC11）的有效选择性抑制剂，IC50值为3nM[1]。HDAC11 是组蛋白脱乙酰酶家族的一个新颖且独特的成员，在特定组织和某些癌细胞系中大量表达[2]。HDAC11具有组蛋白[2]和非组蛋白[3]脱乙酰酶活性，可以通过调节细胞的乙酰化状态，参与染色质重塑和代谢信号通路等细胞活动[3]。FT895作为HDAC11的选择性抑制剂，展现出了的良好的细胞活性和药代动力学特性[4]，是研究 HDAC11 生物学机制的有效工具。
在体外，FT895（10μM）处理A549和H1650细胞24h，可显著降低A549和H1650细胞的细胞迁移能力[5]。FT895（10μM） 处理BMDM（Bone Marrow Derived Macrophage，骨髓来源巨噬细胞） 细胞1h，可显著提升BMDM细胞的杀菌效率[6]。
在体内，FT895（10mg/kg/day）腹腔注射处理C57BL/6J小鼠5天，FT895通过对HDAC11的抑制作用，促进了小鼠体内脂肪组织中线粒体内膜转运蛋白UCP1（Uncoupling protein 1）的表达，最终表现为小鼠核心体温升高[7]。FT895（50mg/kg/day）腹腔注射处理C57BL/6小鼠天7天，FT895通过抑制HDAC11的活性，上调了抗炎因子 IL-10 （Interleukin-10）的表达，促进了抗炎反应并减少了小鼠体内肠道病毒 EV71 的复制[8]。