Our previous study reported that SKLB-23bb, an orally bioavailable HDAC6-selective inhibitor, exhibited superior antitumor efficiency both in vitro and in vivo in comparison with ACY1215, a HDAC6-selective inhibitor recently in phase II clinical trial. This study focused on the mechanism related to the activity of SKLB-23bb. We discovered that despite having HDAC6-selective inhibition equal to ACY1215, SKLB-23bb showed cytotoxic effects against a panel of solid and hematologic tumor cell lines at the low submicromolar level. Interestingly, in contrast to the reported HDAC6-selective inhibitors, SKLB-23bb was more efficient against solid tumor cells. Utilizing HDAC6 stably knockout cell lines constructed by CRISPR–Cas9 gene editing, we illustrated that SKLB-23bb could remain cytotoxic independent of HDAC6 status. Investigation of the mechanism confirmed that SKLB-23bb exerted its cytotoxic activity by additionally targeting microtubules. SKLB-23bb could bind to the colchicine site in β-tubulin and act as a microtubule polymerization inhibitor. Consistent with its microtubule-disrupting ability, SKLB-23bb also blocked tumor cell cycle at G2–M phase and triggered cellular apoptosis. In solid tumor xenografts, oral administration of SKLB-23bb efficiently inhibited tumor growth. These results suggested that SKLB-23bb was an orally bioavailable HDAC6 and microtubule dual targeting agent. The microtubule targeting profile enhanced the antitumor activity and expanded the antitumor spectrum of SKLB-23bb, thus breaking through the limitation of HDAC6 inhibitors. Mol Cancer Ther; 17(4); 763–75. ©2018 AACR.

中文翻译：

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SKLB-23bb，一种 HDAC6 选择性抑制剂，通过额外靶向微管表现出卓越的广谱抗肿瘤活性

我们之前的研究报告称，与最近处于 II 期临床试验的 HDAC6 选择性抑制剂 ACY1215 相比，SKLB-23bb 是一种口服生物可利用的 HDAC6 选择性抑制剂，在体外和体内均表现出优异的抗肿瘤效率。本研究侧重于与 SKLB-23bb 活性相关的机制。我们发现尽管具有等同于 ACY1215 的 HDAC6 选择性抑制，但 SKLB-23bb 在低亚微摩尔水平对一组实体和血液肿瘤细胞系显示出细胞毒性作用。有趣的是，与报道的 HDAC6 选择性抑制剂相比，SKLB-23bb 对实体瘤细胞更有效。利用通过 CRISPR-Cas9 基因编辑构建的 HDAC6 稳定敲除细胞系，我们说明 SKLB-23bb 可以保持细胞毒性，而不受 HDAC6 状态的影响。机制研究证实 SKLB-23bb 通过额外靶向微管发挥其细胞毒活性。SKLB-23bb 可以与 β-微管蛋白中的秋水仙碱位点结合，起到微管聚合抑制剂的作用。与其微管破坏能力一致，SKLB-23bb 还在 G2-M 期阻断肿瘤细胞周期并引发细胞凋亡。在实体瘤异种移植物中，口服 SKLB-23bb 可有效抑制肿瘤生长。这些结果表明 SKLB-23bb 是一种口服生物可利用的 HDAC6 和微管双重靶向剂。微管靶向谱增强了SKLB-23bb的抗肿瘤活性并扩大了抗肿瘤谱，从而突破了HDAC6抑制剂的局限性。摩尔癌症治疗; 17(4); 763-75。©2018 AACR。