JOURNAL OF MEDICINAL CHEMISTRY
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2023
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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
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
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2025
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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
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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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
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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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
Theranostics
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2024
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IF 12.4
Zhiyong Shi,Miaomiao Liu,Xiaowen Zhang,Jingyang Wang,Junwei Zhang,Zeyan Peng,Li Meng,Ruijing Wang,Lihong Guo,Qiang Zhang,Jing Li,Liang Yang,Jie Liu,Yang Xu,Jie Yan,Jianlin Cui,Shan Ren,Yang Gao,Yanming Wang,Zhi Qi
Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo . Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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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
JOURNAL OF MOLECULAR STRUCTURE
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2021
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IF 3.196
Haiping Zhou,Junhao Jiang,Jinyu Lu,Dongzhi Ran,Zongjie Gan
Dual or multiple-targeting inhibition of oncogenic targets in a single molecule could be an alternative approach to drug combinations. Previous studies have revealed that histone deacetylases (HDAC) inhibitor in combination with janus kinase (JAK) inhibitor could exhibit synergistically anti-proliferative effects in cancer treatment. Herein, we presented a novel series of 2,4-dianilinopyrimidine derivatives, which could simultaneously inhibit JAK2 and HDAC1. Among which, 7l was found to be the most potent compound and displayed balanced inhibitory activity against HDAC1 (IC 50 = 1.9 nM) and JAK2 (IC 50 = 0.5 nM), respectively. 7l also demonstrated good antiproliferative activity against tested cancer cell lines (A549, HepG-2, MDA-MB-231 and Jurkat). Moreover, flow cytometric analysis showed that 7l induced apoptosis and cell cycle arrest in a dose-dependent manner, and the insight into mechanisms of 7l indicated that it could decrease the phosphorylation of STAT-3 and promote histone acetylation. In conclusion, these results together suggested that 7l would be a promising lead candidate and deserved further research and development.
研究领域:
药理学
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肿瘤学
·
药物化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）