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Ref Type Journal Article
PMID (29610282)
Authors Wang F, Zheng L, Yi Y, Yang Z, Qiu Q, Wang X, Yan W, Bai P, Yang J, Li D, Pei H, Niu T, Ye H, Nie C, Hu Y, Yang S, Wei Y, Chen L
Title SKLB-23bb, A HDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules.
Journal Molecular cancer therapeutics
Vol 17
Issue 4
Date 2018 Apr
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SKLB-23bb SKLB-23bb 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SKLB-23bb HDAC Inhibitor 38 SKLB-23bb is a selective HDAC6 inhibitor, which may result in disruption of microtubule polymerization, inhibition of the cell-cycle, and induction of apoptosis (PMID: 29610282).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon cancer not applicable SKLB-23bb Preclinical - Cell line xenograft Actionable In a preclinical study, SKLB-23bb treatment resulted in antitumor efficacy in colon cancer cells, demonstrating decreased colony formation in vitro and inhibition of tumor growth in cell line xenograft models (PMID: 29610282). 29610282
Unknown unknown B-cell lymphoma not applicable SKLB-23bb Preclinical - Cell line xenograft Actionable In a preclinical study, SKLB-23bb treatment inhibited tumor growth in B-cell lymphoma xenograft models (PMID: 29610282). 29610282
Unknown unknown ovarian carcinoma not applicable SKLB-23bb Preclinical - Cell line xenograft Actionable In a preclinical study, SKLB-23bb treatment resulted in antitumor efficacy in ovarian carcinoma cells, demonstrating decreased colony formation in vitro and inhibition of tumor growth in cell line xenograft models (PMID: 29610282). 29610282
Unknown unknown breast cancer not applicable SKLB-23bb Preclinical - Cell line xenograft Actionable In a preclinical study, SKLB-23bb treatment inhibited tumor growth in breast cancer xenograft models (PMID: 29610282). 29610282