Article
Chemistry, Medicinal
Jinbo Huang, Jun Zhang, Wenchao Xu, Qiong Wu, Rongsheng Zeng, Zhichao Liu, Wenhui Tao, Qian Chen, Yongqing Wang, Wei-Guo Zhu
Summary: This study reports the design and synthesis of highly potent proteolysis targeting chimeric small molecules that effectively induce the degradation of the epigenetic regulator histone deacetylase 8 (HDAC8). The small molecule SZUH280 was found to inhibit cancer cell growth by promoting HDAC8 protein degradation even at low concentrations. Mechanistic studies revealed that SZUH280 also hampers DNA damage repair, leading to increased cellular radiosensitization.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Kairui Yue, Simin Sun, Geng Jia, Mengting Qin, Xiaohan Hou, C. James Chou, Chao Huang, Xiaoyang Li
Summary: This study reports the development of a highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which exhibits superior pharmacokinetic properties compared to current hydroxamic acid inhibitors. Structure-activity relationship analysis reveals that the presence of an ethyl group substituent in the hydrazide-based ZBG and a cap group with increased rigidity and volume enhance the HDAC6 selectivity of the designed compounds. The representative inhibitor 35m demonstrates potent HDAC6 inhibitory activity and improved pharmacokinetic properties compared to hydroxamic acid-based HDAC6 inhibitors Tubastatin A and ACY1215. Furthermore, low-dose 35m effectively decreases LPS-induced IL-1 beta release by blocking the activation of NLRP3, indicating its potential as an orally active therapeutic agent for NLRP3-related diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yiying Wei, Xinxin Xu, Minchuan Jiang, Yongxing Wang, Yang Zhou, Zhen Wang, Zhang Zhang, Fengtao Zhou, Ke Ding
Summary: A new selective GSPT1 degrader was developed, which could effectively degrade GSPT1 and showed good selectivity in the global proteomic profiling study. The compound also displayed good antiproliferative activities and induced cell cycle arrest and apoptosis in U937 cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Danli Zhou, Yingying Zuo, Zhengying Pan
Summary: This study reports the development of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy, which holds great therapeutic potential for human autoimmune diseases and T-cell malignant lymphomas. Two representative compounds, 23 and 28, demonstrated potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays confirmed the high selectivity of compounds 23 and 28 as ITK degraders. Compound 28 exhibited efficient, rapid, and prolonged ITK degradation in mice, along with significant suppression of IL-2 secretion. It is the first effective and highly selective ITK degrader, serving as a valuable tool compound for further investigation of ITK degradation in human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xufen Yu, Jia Xu, Yudao Shen, Kaitlyn M. Cahuzac, Kwang-Su Park, Brandon Dale, Jing Liu, Ramon E. Parsons, Jian Jin
Summary: In this study, we reported a potent AKT degrader MS21 and its structure-activity relationship (SAR) studies. Additionally, we discovered another VHL-recruiting AKT degrader MS143 with similar efficacy as MS21, as well as a novel CRBN-recruiting PROTAC MS5033. These compounds effectively degraded AKT by hijacking the ubiquitin-proteasome system and showed significant inhibition of cell growth in multiple cancer cell lines. Furthermore, they exhibited good plasma exposure levels in mice and were suitable for in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Daqiang Li, Zhuo Zhang, Yalei Li, Xinyi Wang, Hanyue Zhong, Huajie Yang, Yong Xi, Hongchun Liu, Aijun Shen, Youhong Hu
Summary: A series of novel benzamide derivatives were designed and synthesized from the pyridazinone scaffold. Among them, (S)-17b showed potent inhibitory activity against human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line in vitro. Furthermore, (S)-17b demonstrated excellent in vivo antitumor activity in SKM-1 xenograft models, and showed better efficacy on mouse models with intact immune system compared to those with thymus deficiencies. This novel compound (S)-17b may serve as a promising drug candidate for further investigation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Wenli Fan, Lin Zhang, Xuejiang Wang, Haiyong Jia, Lei Zhang
Summary: In this study, pharmacophores of phenanthridine were incorporated into HDAC inhibitors, and fatty and aromatic linkers were evaluated for solubility and activity. Compounds with aromatic linker showed better activities than those with fatty linker. Molecule Fb-4 exhibited promising anticancer potency by inducing G2/M phase arrest and apoptosis in MCF-7 cells, suggesting its potential as a lead compound for further drug design.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Yiming Chen, Lihui Zhang, Lin Zhang, Qixiao Jiang, Lei Zhang
Summary: Through structural modification, a HDAC inhibitor (I13) with high anticancer activity was discovered, showing promising inhibitory and antiproliferative potencies in in vitro investigations and cancer cell screenings. The compound also demonstrated potential for inhibiting tumor growth in animal models.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Ming-jun Yu, Chao Li, Meng He, Yu-ting Zhu, Rui Yang, Sheng-song Deng, Xiao-ming Meng, Ri-sheng Yao
Summary: Novel Pd176252 analogues, specifically 5a and 6e, showed better anti-proliferation activity against various cancer cell lines compared to Pd176252, with potential synergistic effects when combined with a histone deacetylase inhibitor. These compounds exhibit potent anticancer activity by inducing apoptosis and binding to GRPR.
MEDICINAL CHEMISTRY RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Chunlong Zhao, Deng Chen, Fengzhi Suo, Rita Setroikromo, Wim J. Quax, Frank J. Dekker
Summary: Aberrations in HDAC8 functions are closely linked to various diseases, and development of HDAC8 degradation inducers may be more promising than HDAC8 inhibitors. Using the PROTAC strategy, we developed a selective and potent HDAC8 degradation inducer CT-4 with single-digit nano-molar DC50 values and over 95% Dmax in both MDA-MB-231 cells and T-cell leukemia cells. CT-4 showed potent anti-migration activity and limited anti-proliferative activity in MDA-MB-231 cells, while effectively inducing apoptotic cell death in Jurkat cells. These findings suggest that the development of HDAC8 degradation inducers holds great potential for the treatment of HDAC8-related diseases.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Junius Eugene Thomas, Mi Wang, Wei Jiang, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: The study describes the design, synthesis, and evaluation of potent PROTAC degraders (JET-209) targeting the transcriptional coactivators CBP and p300. JET-209 achieved high degradation potency for CBP and p300 in leukemia cell lines and demonstrated inhibition of tumor growth in xenograft models. JET-209 shows promise as a lead compound for developing CBP/p300 degraders for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Ling Li, Yinrong Wu, Zichao Yang, Chenglong Xu, Huiting Zhao, Jin Liu, Jingxuan Chen, Jianjun Chen
Summary: A series of KRAS G12C-targeting PROTACs were designed and synthesized, with compound KP-14 showing the highest degrading capability in NCI-H358 cancer cells. KP-14 bound to KRAS G12C through the acrylamide warhead and recruited E3 ligase CRBN, leading to rapid and sustained degradation of KRAS G12C and suppression of the MAPK signaling pathway in cancer cells.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Fengling Liu, Chunxi Liu, Qipeng Chai, Chunlong Zhao, Hongwei Meng, Xia Xue, Tso-pang Yao, Yingjie Zhang
Summary: In our previous research, a compound named 1 showed significant anti-tumor activity due to its HDAC inhibitory and NO-donating properties. Further study revealed that compound 1 could increase acetyl histones and acetyl & alpha;-tubulin levels by irreversibly inhibiting class I HDACs and HDAC6. Modification of compound 1 led to the development of compound 4, which selectively and irreversibly inhibited intracellular HDAC6 and exhibited improved therapeutic index compared to ACY-241.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Chen Chen, Xue Li, Huajun Zhao, Meng Liu, Jintong Du, Jian Zhang, Xinying Yang, Xuben Hou, Hao Fang
Summary: The combined use of a DNA minor groove binder and a histone deacetylase (HDAC) inhibitor has shown a synergistic antiproliferation effect. A new series of benzimidazole-hydroxamate hybrids were designed and synthesized to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory activities but also showed potent antiproliferation activities against tumor cells. Importantly, these compounds demonstrated good in vivo antitumor efficacies and reshaped the tumor immune microenvironment by promoting antigen presentation, activating T cells, and polarizing tumor-infiltrating macrophages with antitumor activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Wenjuan Zhang, Pengyun Li, Shiyang Sun, Changkai Jia, Ning Yang, Xiaomei Zhuang, Zhibing Zheng, Song Li
Summary: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC), but drug resistance and side effects are the main challenges. Researchers designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders, and found that compounds 13a and 13b can effectively induce cell apoptosis, cell cycle arrest, and inhibit downstream signaling pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Han Yao, Wenbin Xu, Yajing Liu, Zhijie Cao, Jia Wen, Mi Zhang, Zhen Wu, Xiaojun Yan, Zishan Jiao, Zijing Zhang, Jianyuan Chen, Meng Zhang, Wei-Guo Zhu, Donglai Wang
Summary: The oncoprotein SET contributes to malignant tumors through multiple mechanisms, and its regulation in cancer cells is not well understood. This study reveals that the tumor suppressor p53 transcriptionally represses SET expression and stimulates PP2A phosphatase activity. The interaction between SET and PP2A can be targeted to enhance p53 activation and achieve synergistic tumor suppression. These findings provide mechanistic insights and a potential strategy for cancer therapy.
SCIENCE CHINA-LIFE SCIENCES
(2023)
Article
Cell Biology
Meiting Li, Jiannan Xiong, Liqian Yang, Jie Huang, Yu Zhang, Minghui Liu, Lina Wang, Jianguo Ji, Ying Zhao, Wei-Guo Zhu, Jianyuan Luo, Haiying Wang
Summary: The study reveals a new function of p62 in base excision repair, distinct from its known functions. Loss of p62 impairs repair capacity and increases cancer cell sensitivity to alkylating and oxidizing agents. Therefore, targeting p62 may have potential for cancer therapeutics.
Review
Immunology
Tingting Yang, Chanping You, Shuhui Meng, Zhengquan Lai, Weipeng Ai, Jun Zhang
Summary: Viral oncogenes can modulate cellular metabolic reprogramming to drive malignant transformation of normal epithelia cells. Understanding the dysregulation of viral oncogene-mediated signaling transduction in metabolic reprogramming may offer new therapeutic targets for virus-associated cancer treatment. This review focuses on elucidating how EBV infection and its encoded oncoproteins alter metabolic reprogramming to promote malignancy, and provides a new perspective on the interplay between EBV infection and metabolic pathways, offering a potential therapeutic intervention strategy for EBV-associated malignant diseases.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Lingyu Qiu, Chen Liang, Yidong Zheng, Huayu Kang, Aiyue Chen, Chunlin Chen, Xinlong Wang, Jielin Yang, Qiongfang Fang, Xinjie Hui, Yueming Hu, Zewei Chen, Ou Sha, Wei-Guo Zhu, Yejun Wang
Summary: This research systematically investigates stable expressed genes (SEGs) in humans at the single-cell level and observes their specificity in development, tissue, and cell types. The study identifies a list of 408 spatial-temporal SEGs and finds development-specific SEGs as well as tissue-specific SEGs with immune and RNA splicing functions. The research also explores the application of SEGs in cell decomposition and accurately predicts the proportions of major immune cells in peripheral blood samples.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Yang-Liu Song, Ming-Hui Yang, Si Zhang, Hao Wang, Kun-Lun Kai, Chun-Xia Yao, Fei-Fei Dai, Meng-Jiao Zhou, Jin-Biao Li, Zhi-Ru Wei, Zhongnan Yin, Wei-Guo Zhu, Lixiang Xue, Ming-Xi Zang
Summary: This study reveals that GATA-4 acts as a molecular switch for the regulation of miR-29a expression. It recruits polycomb group proteins like EZH2 to negatively regulate miR-29a in undifferentiated C2C12 myoblast cells. In poorly differentiated rhabdomyosarcoma cells, EZH2 still binds to the miR-29a promoter with GATA-4 to mediate transcriptional repression of miR-29a. However, during re-differentiation of rhabdomyosarcoma cells, EZH2 is displaced from the miR-29a promoter, leading to the activation of miR-29a and promoting myogenic differentiation.
Article
Oncology
Wing Chung Tang, Sai Wah Tsao, Gareth E. Jones, Xiong Liu, Ming Han Tsai, Henri-Jacques Delecluse, Wei Dai, Chanping You, Jun Zhang, Shaina Chor Mei Huang, Manton Man-hon Leung, Tengfei Liu, Yick Pang Ching, Honglin Chen, Kwok Wai Lo, Xin Li, Chi Man Tsang
Summary: This study reveals the interaction between TNF alpha released by macrophages and EBV-encoded LMP1 in driving the mobilization of invadopodia in EBV-associated nasopharyngeal carcinoma (NPC). The mobilizing invadopodia exhibit lateral movements and enhanced degradative power, transforming from dot-like digestion patterns to dendrite-like patterns. EBV infection sensitizes NPC cells to form mobilizing invadopodia in a TNF alpha-rich tumor microenvironment.
JOURNAL OF PATHOLOGY
(2023)
Article
Multidisciplinary Sciences
Ming Tang, Guofang Chen, Bo Tu, Zhiyi Hu, Yujia Huang, Christopher C. DuFort, Xiaoping Wan, Zhiyong Mao, Yongzhong Liu, Wei-Guo Zhu, Wen Lu
Summary: DDR has different effects on cancer susceptibility and drug resistance. Recent studies showed that DDR inhibitors impact immune surveillance, however, the underlying mechanism is poorly understood. This study reveals that methyltransferase SMYD2 plays a crucial role in nonhomologous end joining repair (NHEJ), promoting tumor cell adaptability to radiotherapy. SMYD2 is mobilized to chromatin upon DNA damage and methylates Ku70, leading to increased recruitment of Ku70/Ku80/DNA-PKcs complex. Inhibition of SMYD2 or knockdown of SMYD2 results in persistent DNA damage and improper repair, leading to cytosolic DNA accumulation and activation of cGAS-STING pathway, triggering antitumor immunity by infiltration and activation of cytotoxic CD8+ T cells. This study reveals a novel role of SMYD2 in regulating NHEJ pathway and innate immune responses, suggesting SMYD2 as a promising therapeutic target for cancer treatment.
Article
Biochemistry & Molecular Biology
Jun Zhang, Feng Chen, Yuan Tian, Wenchao Xu, Qian Zhu, Zhenhai Li, Lingyu Qiu, Xiaopeng Lu, Bin Peng, Xiangyu Liu, Haiyun Gan, Baohua Liu, Xingzhi Xu, Wei-Guo Zhu
Summary: In response to DNA damage, pyruvate dehydrogenase 1 & alpha; (PDHE1 & alpha;) rapidly generates acetyl-CoA by catalyzing pyruvate metabolism, which is necessary for chromatin relaxation and histone acetylation around double-strand breaks (DSBs). PDHE1 & alpha; is recruited to chromatin in a polyADP-ribosylation-dependent manner and enhances DSB repair efficiency, genome stability, and cancer cell resistance to DNA-damaging treatments in vitro and in vivo.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Lingyu Qiu, Wenchao Xu, Xiaopeng Lu, Feng Chen, Yongcan Chen, Yuan Tian, Qian Zhu, Xiangyu Liu, Yongqing Wang, Xin-Hai Pei, Xingzhi Xu, Jun Zhang, Wei-Guo Zhu
Summary: HDAC6 regulates DNA damage signaling by controlling the mismatch repair and nucleotide excision repair pathways. It negatively regulates DNA double-strand break (DSB) repair in an enzyme activity-independent manner. HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168, and DSBs lead to the degradation of HDAC6 and the restoration of the interaction between RNF168 and H2A/H2A.X, facilitating the recruitment of DSB repair factors to chromatin and subsequent DNA repair.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Oncology
Meng Yuan, Bo Tu, Hengchao Li, Huanhuan Pang, Nan Zhang, Minghe Fan, Jingru Bai, Wei Wang, Zhaoqi Shu, Christopher C. DuFort, Sihan Huo, Jie Zhai, Ke Yao, Lina Wang, Haoqiang Ying, Wei-Guo Zhu, Deliang Fu, Zeping Hu, Ying Zhao
Summary: The study demonstrates that cancer-associated fibroblasts in the pancreatic tumor microenvironment secrete nucleosides through autophagy in an NUFIP1-dependent manner, thereby inducing glucose consumption under glutamine-deprived conditions and promoting tumor growth.
Letter
Biochemistry & Molecular Biology
Yuxin Shu, Nanfei Yang, Nan Cheng, Zhengyun Zou, Wenlong Zhang, Yuncheng Bei, Qian Shi, Menghao Qin, Wei-Guo Zhu, Pingping Shen
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2022)
Article
Chemistry, Medicinal
Jinbo Huang, Jun Zhang, Wenchao Xu, Qiong Wu, Rongsheng Zeng, Zhichao Liu, Wenhui Tao, Qian Chen, Yongqing Wang, Wei-Guo Zhu
Summary: This study reports the design and synthesis of highly potent proteolysis targeting chimeric small molecules that effectively induce the degradation of the epigenetic regulator histone deacetylase 8 (HDAC8). The small molecule SZUH280 was found to inhibit cancer cell growth by promoting HDAC8 protein degradation even at low concentrations. Mechanistic studies revealed that SZUH280 also hampers DNA damage repair, leading to increased cellular radiosensitization.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
