SKLB-23bb, A HDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules.

Abstract

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.

• Authors: Fang Wang, Li Zheng, Yuyao Yi, Zhuang Yang, Qiang Qiu, Xiaoyan Wang, Wei Yan, Peng Bai, Jianhong Yang, Dan Li, Heying Pei, Ting Niu, Haoyu Ye, Chunlai Nie, Yiguo Hu, Shengyong Yang, Yuquan Wei, Lijuan Chen
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 4 Pg. 763-775 (04 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 29610282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Butyrates
• Histone Deacetylase Inhibitors
• Quinazolines
• Tubulin Modulators
• HDAC6 protein, human
• Histone Deacetylase 6

Topics

• Animals
• Apoptosis
• Butyrates (pharmacology)
• Cell Cycle
• Cell Movement
• Cell Proliferation
• Female
• Histone Deacetylase 6 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Microtubules (drug effects, metabolism, pathology)
• Neoplasms (drug therapy, enzymology, pathology)
• Quinazolines (pharmacology)
• Tubulin Modulators (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays