Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects

Zhu, Huajian; Tan, Yuchen; He, Chen; Liu, Yang; Duan, Yiping; Zhu, Wen-Jian; Zheng, Tiandong; Li, Dahong; Xu, Jinyi; Yang, Dong‐Hua; Chen, Zhe‐Sheng; Xu, Shengtao

doi:10.1021/acs.jmedchem.2c00681

Cited by 13 publications

(2 citation statements)

References 57 publications

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“…Some prodrug forms used to improve aqueous solubility and PK profiles could continue to be investigated. Furthermore, with the advances in innovative strategies of drug discovery, it is feasible to develop novel dual-target tubulin inhibitors [110][111][112] to improve therapeutic effects and overcome drug resistance.…”

Section: Future Perspectivementioning

confidence: 99%

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Weng

Zhu

et al. 2023

Future Med. Chem.

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Microtubules, formed by α- and β-tubulin heterodimer, are considered as a major target to prevent the proliferation of tumor cells. Microtubule-targeted agents have become increasingly effective anticancer drugs. However, due to the relatively sophisticated chemical structure of taxane and vinblastine, their application has faced numerous obstacles. Conversely, the structure of colchicine binding site inhibitors (CBSIs) is much easier to be modified. Moreover, CBSIs have strong antiproliferative effect on multidrug-resistant tumor cells and have become the mainstream research orientation of microtubule-targeted agents. This review focuses mainly on the recent advances of CBSIs during 2017–2022, attempts to depict their biological activities to analyze the structure–activity relationships and offers new perspectives for designing next generation of novel CBSIs.

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Section: Future Perspectivementioning

confidence: 99%

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Weng

Zhu

et al. 2023

Future Med. Chem.

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“…Histone deacetylases (HDACs) are an important component of epigenetic factors to catalyze the removal of acetyl and acyl groups from the modified ε-amino moiety of lysine in histone tails, thereby playing an essential role in the regulation of target gene expression. , The dysregulation of HDAC expression has been implicated in various cancer types, making HDACs attractive targets for cancer therapy. − Correspondingly, there were many endeavors that contributed to the development of HDAC inhibitors (HDACis) as a new therapeutic treatment, including pan-HDACis, − subtype-selective HDACiss, − and dual-target inhibitors based on HDAC. − Notably, five HDACis, namely, vorinostat (SAHA), belinostat, panobinostat, romidepsin, and chidamide, have been approved for the treatment of T-cell lymphoma and multiple myeloma (Figure ). Besides, several HDACis have been launched in clinical trials; for instance, abexinostat was in the phase III stage of a clinical trial for the treatment of renal carcinoma and lymphoma.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma

Lai

et al. 2023

J. Med. Chem.

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The development of histone deacetylase (HDAC) inhibitors for treating hematologic malignancies has been widely investigated, while their role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we employed a scaffold-hopping design and a multicomponent synthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29 compounds achieved with flexible linkers and zinc-binding groups, wherein compound 12k was identified as a promising candidate with good HDAC inhibitory activity, pharmacokinetic profiles, and potency. It exhibited significant therapeutic efficacy in HCC cell lines (IC 50 = 30 nM for Bel-7402) and xenograft models (76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for 14 days) and was found to upregulate the acetylation of histone H3 and α-tubulin, leading to apoptosis and autophagy in HCC models. Molecular docking studies indicated a unique T-shaped conformation of 12k with the catalytic domain of HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for HCC.

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Discovery of a novel Coumarin-Dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activities

Song

Wang

et al. 2023

Bioorganic Chemistry

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Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects

Cited by 13 publications

References 57 publications

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma

Discovery of a novel Coumarin-Dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activities

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