Curriculum vitae of HDAC6 in solid tumors

Zheng, Yi-Chao; Kang, Huifang; Wang, Bo; Zhu, Yuan-Zai; Mamun, M. A. A.; Zhao, Longfei; Nie, Hai-Qian; Liu, Ying; Zhao, Lijuan; Zhang, Xiaonan; Gao, Mei-Mei; Jiang, Dandan; Liu, Hong‐Min; Gao, Ya

doi:10.1016/j.ijbiomac.2023.123219

Cited by 15 publications

(8 citation statements)

References 139 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HDAC, JAK, and BRD4 inhibitory activities of target compounds were preliminarily evaluated by determining their inhibitory rates against HDAC1, JAK1, and BRD4-BD1 at single concentrations, with the approved HDAC inhibitor SAHA and JAK/BRD4 dual inhibitor Fedratinib as the positive controls. In addition, their inhibitory rates against HDAC6, a potential therapeutic target for solid tumors, were also determined.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer

Zhao,

Zhang,

Zhang

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

Multitarget HDAC inhibitors capable of simultaneously blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based multitarget HDAC inhibitors were rationally designed, synthesized, and biologically evaluated, among which compound 25a p stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound 25a p led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3 signaling pathway, which was validated by hyper-acetylation of histone and α-tubulin, hypo-phosphorylation of STAT3, downregulation of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects of 25a p contributed to its robust antitumor response, including potent antiproliferative activity, remarkable apoptosis-inducing activity, and inhibition of colony formation. Notably, 25a p possessed an acceptable therapeutic window between normal and cancerous cells, desirable in vitro metabolic stability in mouse microsome, and sufficient in vivo exposure via intraperitoneal administration. Additionally, the in vivo antitumor potency of 25a p was demonstrated in an MDA-MB-231 xenograft model.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer

Zhao,

Zhang,

Zhang

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…HDAC6, the singular of the HDAC family situated in the cytoplasm, functions specifically to catalyze the deacetylation of nonhistone substrates ( Zheng et al, 2023 ) and is involved in many physiological or pathological mechanisms in a wide range of diseases ( Li et al, 2023a ). Inhibitors of HDAC6, which exhibit immune modulatory effects in preclinical models, have a selective targeting effect without significant toxicity and prolong the stabilization of the disease in some patients ( Tsimberidou et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Novel mechanistic study of HDAC6 regulation of rheumatoid arthritis via CMA: exploring potential therapeutic targets

Lin,

Lai,

Zheng

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Objective:Rheumatoid arthritis (RA) is a systemic autoimmune disease. Its pathogenesis has not yet been clarified, so it is urgent to explore therapeutic targets. Here, we clarified the role of HDAC6 in the mechanism of action of RA through mediating chaperone-mediated autophagy (CMA) to provide a clinical treatment of RA.Methods:We used rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis mice (CIA mice) as models of RA and pharmacological inhibitors as well as genetic interference with adeno-associated viruses to reduce the expression of HDAC6. We explored the influence of CAY10603 on RA-FLS proliferation and inflammation, as well as the expression of proteins related to the CMA signaling pathway. CIA model was constructed using DBA/1J mice. Arthritis symptoms in CIA mice were evaluated, and the expression and localization of CMA-related proteins in mouse ankle joints were examined.Results:CAY10603 inhibited proliferation as well as the level of the molecular chaperone autophagy in RA-FLS. HDAC6 shRNA significantly reduced the clinical signs of arthritis in CIA mice, as did the expression of HDAC6 in the serum and ankle synovial tissues of CIA mice. Finally, it significantly inhibited the level of Hsc70 and LAMP-2A, which are involved in the CMA signaling pathway, in ankle joint tissues.Conclusion:Downregulation of HDAC6 may inhibit CMA and thereby ameliorate RA.

show abstract

“…HDAC6 not only modifies and regulates histones, but also acts on some non-histone [ 12 ]. HDAC6 is involved in the regulation of tumor cell proliferation, apoptosis, migration and invasion, autophagy, DNA damage response and immune regulation [ 13 – 15 ]. As a result, HDAC6 can be considered as a tumor target.…”

Section: Introductionmentioning

confidence: 99%

HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy

Wen,

Ye,

et al. 2024

Cancer Immunol Immunother

View full text Add to dashboard Cite

The search for effective combination therapy with immune checkpoint inhibitors (ICI) has become important for cancer patients who do not respond to the ICI well. Histone deacetylases (HDACs) inhibitors have attracted wide attention as anti-tumor agents. ACY-1215 is a selective inhibitor of HDAC6, which can inhibit the growth of a variety of tumor. We previously revealed that HDAC family is highly expressed in colorectal cancer specimens and mouse models. In this study, ACY-1215 was combined with anti-PD1 to treat tumor-bearing mice associated with colorectal cancer. ACY-1215 combined with anti-PD1 effectively inhibited the colorectal tumor growth. The expression of PD-L1 in tumor of mice were inhibited by ACY-1215 and anti-PD1 combination treatment, whereas some biomarkers reflecting T cell activation were upregulated. In a co-culture system of T cells and tumor cells, ACY-1215 helped T cells to kill tumor cells. Mechanically, HDAC6 enhanced the acetylation of STAT1 and inhibited the phosphorylation of STAT1, thus preventing STAT1 from entering the nucleus to activate PD-L1 transcription. This study reveals a novel regulatory mechanism of HDAC6 on non-histone substrates, especially on protein acetylation. HDAC6 inhibitors may be of great significance in tumor immunotherapy and related combination strategies.

show abstract

Curriculum vitae of HDAC6 in solid tumors

Cited by 15 publications

References 139 publications

Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer

Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer

Novel mechanistic study of HDAC6 regulation of rheumatoid arthritis via CMA: exploring potential therapeutic targets

HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy

Contact Info

Product

Resources

About