JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Yuanjiang Wang,Jianluo Zhang,Kun Li,Shengjin Xia,Shaohua Gou
In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.
研究领域:
药理学
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肿瘤学
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分子生物学
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DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Yahui Huang,Na Liu,Zhizhi Pan,Zhuang Li,Chunquan Sheng
Breast cancer is susceptible to Candida infections, and candidiasis has an enhancing effect on the progression and metastasis of tumor. Breast cancer and concurrent candidiasis represent a significant challenge in clinical therapy. Herein, a series of novel small molecule inhibitors simultaneously targeting bromodomain and extra-terminal (BET) and histone deacetylase (HDAC) were designed for combinational treatment of breast cancer and resistant Candida albicans infections. Among them, compounds 13c and 17b exhibited excellent and balanced inhibitory activity against both BET family proteins BRD4 and HDAC1. As compared with BRD4 or HDAC1 inhibitors, dual inhibitors 13c and 17b displayed improved in vivo antitumor efficacy in MDA-MB-231 breast cancer xenograft models. Notably, they synergized with fluconazole (FLC) to effectively reduce the kidney fungal burden in a murine model of disseminated candidiasis. Thus, the BET–HDAC dual inhibitors represented a novel therapeutic strategy for combinational treatment of breast cancer and concurrent candidiasis.
研究领域:
肿瘤学
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医学微生物学
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药物化学
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DOI
PubMed
高影响因子
Clinical and Translational Medicine
·
2020
·Vol. 10
·期 4
·e154
·
IF 7.919
Xiaoxuan Yu,Hui Li,Po Hu,Yingjie Qing,Xiangyuan Wang,Mengyuan Zhu,Hongzheng Wang,Zhanyu Wang,Jingyan Xu,Qinglong Guo,Hui Hui
Background Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor-acute myeloid leukemia (CBF-AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug-resistant characteristic. Our purpose is to evaluate the anti-leukemia effects of Baicalein on CBF-AML and clarify its underlying mechanism. Methods Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT-qPCR were employed to evaluate the distribution of drugs and the change of ATP-binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC-1 and ubiquitin, HSP90 and AML1-ETO, and Ac-p53 and CBFβ-MYH11. AML cell lines and primary AML cells-bearing NOD/SCID mice models were used to evaluate the anti-leukemic efficiency and potential mechanism of Baicalein in vivo. Results Baicalein showed HDAC-1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC-1 was mild, Baicalein could induce the degradation of HDAC-1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1-ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53-mediated apoptosis genes expression. Moreover, CBFβ-MYH11-bound p53 acetylation was restored via HDAC-8 inhibition induced by Baicalein contributing the diminishing of survival of CD34 + inv(16) AML cells. Conclusions These findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF-AML.
研究领域:
肿瘤学
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分子生物学
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药理学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yabing Xin,Can Xiao,Nan Wang,Huidan Wu,Wenjing Kang,Xuetao Chen,Chihong Liu,Qidong You,Zhengyu Jiang,Xiaoke Guo
Acute myeloid leukemia (AML) patients usually exhibit suboptimal responses after receiving single target drug therapy. Simultaneously targeting multiple oncogenic pathways is a promising strategy for cancer treatment. Herein, based on the synergistic antiproliferative capacity of the PIM inhibitor C28 and the HDAC inhibitor SAHA in MV4–11 cells, we developed a series of novel dual PIM/HDAC inhibitors. Among them, compound 22 exhibited potent antiproliferative activity in MV4–11 cells, along with robust inhibitory effects against both PIM1 and HDAC6. Flow cytometry analysis showed that 22 dose-dependently induced apoptosis in MV4–11 cells. Mechanistically, treatment with 22 remarkably induced the cleavage of PARP, thereby initiating apoptosis. Furthermore, 22 demonstrated significant anticancer efficacy (TGI = 81.3%; 50 mg/kg, QD) in the MV4–11 xenograft model without notable toxicity. In conclusion, our study established the therapeutic potential of dual PIM/HDAC inhibitors and provided a tool to elucidate synergistic mechanisms underlying the combined inhibition of these targets.
研究领域:
肿瘤学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Guanlu Long,Xianghan Wang,Xin Chen,Sai Ma,Liangkui Sun,Zhengyu Jiang,Qidong You,Xiaoke Guo
Targeting the WDR5–MLL1 protein–protein interaction (PPI) is considered to be an effective approach for the treatment of MLL-rearranged leukemia. However, interfering with WDR5–MLL1 PPI reduces methylated H3K4 levels and induces a decline in acetylated H3 levels, which may contribute to the suboptimal cellular efficacy of WDR5 inhibitors. We observed that cotreatment with WDR5–MLL1 PPI and HDAC inhibitors augmented the antiproliferative effect in MV-4-11 cells. Thus, a series of dual-target inhibitors was developed by merging the pharmacophores of the WDR5 and HDAC inhibitors. Among the developed inhibitors, compound 32d displayed an 89-fold increase in antiproliferative efficacy and induced potent cell apoptosis by impeding the DNA damage repair signaling pathway. Furthermore, the administration of 30 mg/kg of compound 32d was well tolerated, inhibiting MV-4-11 xenograft growth by 87.1%. Our investigation established the therapeutic effectiveness of the developed WDR5–MLL1/HDAC dual-target inhibitor against acute myeloid leukemia, providing a valuable tool for further exploration of crosstalk between the two targets.
研究领域:
药理学
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肿瘤学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Zhuang Li,Yahui Huang,Jie Tu,Wanzhen Yang,Na Liu,Wei Wang,Chunquan Sheng
Over the past several decades, invasive fungal infections, especially candidiasis, have caused dramatic morbidity and mortality due to ineffective antifungal drugs and severe drug resistance. Herein, new BRD4–histone deacetylase (HDAC) inhibitors were designed to restore the susceptibility of Candida albicans (C. albicans) to fluconazole (FLC). Interestingly, several compounds showed excellent selectivity against fungal HDACs. In particular, compound B2 showed excellent synergistic effect with FLC against resistant C. albicans (FICI = 0.063) with high selectivity against fungal HDACs (SI = 1653) and low cytotoxicity. Compound B2 effectively synergized with FLC and prevented biofilm formation and morphological transition in resistant C. albicans, potentiating the antifungal activity of FLC in vivo and significantly reducing kidney fungal loads. Thus, this drug combination is promising in the treatment of resistant C. albicans infections.
研究领域:
微生物学
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药理学
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传染病学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Churu Mao,Jiebin Fang,Shijie Zou,Yun Huang,Xiaoming Chen,Xia Ding,Zhangyun Fang,Ningjing Zhang,Yijie Lou,Zhe Chen,Wanjing Ding,Zhongjun Ma
Triple-negative breast cancer (TNBC) represents a highly aggressive and heterogeneous malignancy. Currently, multitarget drug approaches present a promising therapeutic approach for TNBC. Utilizing a combinatorial chemistry strategy to construct a virtual screening database, dual ROCK/HDAC-targeting benzothiophene compounds were identified. Notably, compound 10h effectively inhibits ROCK1/2 and HDAC1/2/3/6/8 while demonstrating potent antiproliferative activity against breast cancer cells. In an orthotopic mouse model of breast cancer, 10h significantly suppressed tumor growth without apparent toxicity. Importantly, 10h induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation, and activated T cells, thereby initiating antitumor immunity. In conclusion, compound 10h is a novel dual-target ROCK/HDAC inhibitor that represents a promising treatment strategy for TNBC.
研究领域:
肿瘤学
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药理学
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免疫学
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DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2022
·
IF 3.461
Zi-Xiao Wang,Shuai Wang,Xue-Peng Qiao,Wen-Bo Li,Jian-Tao Shi,Yi-Ru Wang,Shi-Wu Chen
PI3Ks and HDACs play essential roles in the occurrence and progression of leukemia. Herein, a series of novel pyrazin-2(1 H )-one derivatives were rationally designed and synthesized as novel dual PI3K and HDAC inhibitors based on scaffold replacement and heterozygous strategies. Most of the target compounds showed potent inhibitory potency to PI3Kα and HDAC6. Especially, compound 9q displayed PI3Kα and HDAC6 inhibitory with IC 50 values of 372 nM and 4.5 nM, and anti-proliferative activity against MV4-11 cells with IC 50 value of 0.093 ± 0.012 μM. Further mechanistic studies revealed that 9q induced apoptosis, arrested the cell cycle in the G2/M phase, promoted the acetylation of α-tubulin, and blocked the PI3K/AKT/mTOR signal way in MV4-11 cells. All the results demonstrated that 9q was a promising lead candidate for further development of novel PI3K/HDAC dual inhibitors for leukemia treatment.
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DOI
PubMed
高影响因子
International Journal of Clinical and Experimental Pathology
·
2015
·
IF 1.891
Qingwei Zhang,Haiya Wu,Congcong Wen,Fa Sun,Xuezhi Yang,Lufeng Hu
MGCD0103, an isotype-selective HDACi, has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In this study, we developed a serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of intragastric administration of MGCD0103 on rats. The MGCD0103 group rats were given 20, 40, 80 mg/kg of MGCD0103 by intragastric administration each day for 7 days. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of MGCD0103 induced metabolic perturbations. As compared to the control group, the levels of L-alanine, L-isoleucine, and L-leucine of MGCD0103 group decreased. The results indicate that metabolomic methods based on GC-MS may be useful to elucidate side effect of MGCD0103 through the exploration of biomarkers (L-alanine, L-isoleucine, and L-leucine). According to the pathological changes of liver at difference dosage, MGCD0103 is hepatotoxic and its toxity is dose-dependent.
研究领域:
药理学
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代谢组学
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毒理学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Yuxuan Zhu,Ting Yuan,Yuan Zhang,Jianyou Shi,Lan Bai,Xingmei Duan,Rongsheng Tong,Lei Zhong
Purpose Esophageal squamous cell carcinoma (ESCC) is a refractory malignancy with high morbidity and mortality. Thus, there is an urgent need to find effective targets and agents for ESCC treatment. The purpose of this study was to assess the anti-ESCC effects of a pan-histone deacetylase (HDAC) inhibitor AR-42 and its mechanisms of action.Methods Immunohistochemical staining was performed to detect HDAC1 expression in ESCC and adjacent tissue samples. MTT assay, Edu cell proliferation test, flow cytometry, and subcutaneous xenograft were used to assess the anti-ESCC effects of AR-42; furthermore, the antiangiogenic activity of AR-42 was evaluated using endothelial cell migration, invasion, and tube formation assays as well as zebrafish angiogenesis assay. Western blot analysis was performed to explore the underlying mechanism of the anti-ESCC activity of AR-42.Results HDAC1-positive expression was much higher in ESCC cells than in paracancerous tissues, and the elevated HDAC1 expression was a strong indicator of lymph node metastasis and a more advanced TNM stage of ESCC. Moreover, AR-42 potently suppressed ESCC cell growth through cellular proliferation inhibition and apoptosis induction. Moreover, AR-42 displayed a moderate antiangiogenic activity, and it could significantly inhibit the migration, invasion and tubulogenesis of human umbilical vein endothelial cells as well as intersegmental vessel formation in zebrafish at micromolar concentrations. More importantly, the inhibitory activity of AR-42 on ESCC cells and angiogenesis could also be observed in the TE-1 xenograft model. Further studies showed that AR-42 exerts its anti-ESCC effects mainly by upregulating the expression of p21 and blocking the transduction of multiple signaling cascades related to tumor growth, especially Stat3-mediated signaling.Conclusion Overall, AR-42 has significant potency for inhibiting ESCC cell growth and shows moderate effect in suppressing angiogenesis, displaying strong anti-ESCC effects in vitro and in vivo. Thus, AR-42 deserves further evaluation as a potential candidate for ESCC therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF INVESTIGATIVE DERMATOLOGY
·
2020
·
IF 7.143
Xiaoxuan Yu,Hui Li,Mengyuan Zhu,Po Hu,Xiao Liu,Yingjie Qing,Xiangyuan Wang,Hongzheng Wang,Zhanyu Wang,Jingyan Xu,Renxiang Tan,Qinglong Guo,Hui Hui
Cutaneous T-cell lymphomas (CTCLs) represent a rare form of non-Hodgkin lymphomas characterized by an accumulation of malignant CD4 + T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with histone deacetylase (HDAC) 1 and HDAC8, and was subsequently deacetylated to lose its function in CTCL cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on p53 status. However, recent studies have reported that HDAC inhibitors could induce a wide variety of drug-resistant characteristics in cancer cells by regulating ATP-binding cassette transporters. Moreover, we discovered that Baicalein, a natural product, exhibited an inhibitory effect on HDAC1 and HDAC8. Though the inhibition of HDAC1 was mild, Baicalein could induce the degradation of HDAC1 through the ubiquitin proteasome pathway, thereby markedly upregulating the acetylation of histone H3 without promoting ATP-binding cassette transporter gene expression. In terms of the mechanism, Baicalein showed better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC1 and HDAC8 and p53 in T-cell lymphoma cells and identifies a potential and safe natural HDAC inhibitor for the treatment of CTCLs.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS
·
2026
·
IF 6.6
Yaqi Liu,Biao Luo,Yun Xu,Dexiang Liu,Qiujing Wang
Ischemic stroke (IS) remains a leading cause of global disability and mortality, with limited effective anti-inflammatory interventions. Targeting histone deacetylase 3 (HDAC3) to reprogram microglial polarization holds great therapeutic promise, but the HDAC3-specific inhibitor RGFP966 suffers from poor blood-brain barrier (BBB) penetration and systemic toxicity. Herein, we developed a pH-responsive brain-targeted lipid nanoparticle (CD-TLNP@RGFP966) by integrating T7 peptide modification for BBB transcytosis and cinnamaldehyde-α-cyclodextrin (CA-αCD) encapsulation for acidic lesion-triggered drug release. CD-TLNP@RGFP966 exhibited favorable colloidal stability, biosafety, and pH-dependent release behavior. It efficiently crossed the BBB, accumulated in ischemic brain tissue, promoted microglial M2 polarization, attenuated neuroinflammation, reduced infarct volume, and improved neurological function in tMCAO mice. This study provides a novel targeted nanocarrier strategy for the anti-inflammatory treatment of IS.
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产品关联
DOI
PubMed
高影响因子
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