Design, synthesis and evaluation of structural optimization derived HDAC6 isoform-selective inhibitor
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Published on: January 14, 2016
Chen Chen1, Xiaochun Ma2, Yichao Wan3
1Shandong Chengchuang Blue Sea Pharmaceutical Technology Co., Ltd., Jinan,250100, PR China.
Abstract:
In stark contrast to other HDAC isoforms, deletion or inhibition of HDAC6 suppresses cell proliferation without lethality or defective phenotypes, thereby establishing HDAC6 as a compelling anti-cancer target. In pursuit of safe and effective anti-cancer chemotherapy, we preformed three-round structural optimization and developed several potent HDAC6-selective inhibitors. Among these, HDSI-18 exhibited remarkable inhibitory activity (IC50 = 1.6 nM) and exceptional isoform selectivity (over 975-fold) against HDAC6. Further biological evaluations highlighted the promising properties of HDSI-18 in terms of anti-proliferative activity, mitochondrial depolarization, caspase-3 activation, apoptosis induction and druggability (both in vivo and in vitro). This study demonstrated a paradigm for the rational structural optimization of HDAC6 selective inhibitors, which may serve as a beacon for the development of more promiscuous compounds.
Insights
Researchers developed a potent and selective HDAC6 inhibitor, HDSI-18, showing promise for anti-cancer chemotherapy by suppressing cancer cell proliferation without causing toxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase 6 (HDAC6) is a validated anti-cancer target due to its role in cell proliferation.
- Targeting HDAC6 offers a potential therapeutic strategy for cancer treatment.
Purpose of the Study:
- To design and synthesize novel HDAC6-selective inhibitors.
- To evaluate the anti-cancer potential of these inhibitors, focusing on efficacy and selectivity.
Main Methods:
- Structure-based drug design and three rounds of optimization.
- In vitro assays to determine inhibitory activity (IC50) and isoform selectivity.
- In vitro and in vivo studies to assess anti-proliferative effects, apoptosis induction, and druggability.
Main Results:
- HDSI-18 demonstrated potent HDAC6 inhibition (IC50 = 1.6 nM) with exceptional selectivity (>975-fold).
- HDSI-18 exhibited significant anti-proliferative activity, induced apoptosis via caspase-3 activation and mitochondrial depolarization.
- Promising in vitro and in vivo druggability profiles were observed for HDSI-18.
Conclusions:
- HDSI-18 is a highly potent and selective HDAC6 inhibitor with significant anti-cancer properties.
- This study provides a rational design strategy for developing novel HDAC6-targeted cancer therapies.
