Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome
Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome
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DOI：
10.1021/acschemneuro.8b00600
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发表时间：
2019-03-01
影响因子：
5
通讯作者：
Jope, Richard S.
中科院分区：
文献类型：
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作者：
Kozikowski, Alan P.;Shen, Sida;Jope, Richard S.
脆性X综合征(FXS)需要疾病修正疗法，因为目前还没有有效的治疗或治愈方法。在此，我们报道了一种基于四氢喹啉的选择性组蛋白脱乙酰酶6(HDAC6)抑制剂SW-100，它的药理和ADMET性质，以及它在FXS小鼠模型Fmr1-1-小鼠中改善记忆能力的能力。这种小分子表现出良好的脑穿透性，对HDAC6(IC50=2.3 nM)的抑制具有低纳摩尔效力，比所有其他I、II和IV类HDAC亚型至少有1000倍的选择性。此外，通过抑制HDAC6的α-微管蛋白脱乙酰酶结构域(CD2)，在细胞中，SW-100上调α-微管蛋白乙酰化而不影响组蛋白乙酰化，并选择性地恢复Fmr1(-/-)小鼠海马区受损的乙酰化α-微管蛋白水平。最后，SW-100改善了Fmr1(-/-)小鼠的几种记忆和学习障碍，从而模拟了与FXS相关的智能缺陷，从而为寻求基于HDAC6的疗法治疗这种罕见疾病提供了强有力的理由。
Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-1- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the alpha-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates alpha-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated alpha-tubulin levels in the hippocampus of Fmr1(-/-) mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1(-/-) mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.