JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Wei Zhu,Pei Zhao,Tingting Liu,Feng Gao,Qi Li,Xin Cai,Man Zhang,Alex Aliper,Feng Ren,Alex Zhavoronkov,Xiao Ding
The dual inhibition of SIK2/3 has been considered as a potential treatment approach for MEF2C-high acute myeloid leukemia (AML). Although diverse scaffolds of pan-SIK or SIK2/3 inhibitors have been reported, few of them showed sufficient in vitro or in vivo antitumor activity. Based on the proposed binding mode of the hit molecule (7), chemical space in the solvent/P-loop region was explored via fragment growing/replacement, supported by the generative chemistry platform. Further SAR exploration and ADME optimization led to the discovery of 7s, which exhibited excellent potency and strong selectivity in MEF2C high-expression cell lines over MEF2C-low cell lines. Moreover, oral administration of 7s was found to demonstrate significant tumor growth inhibition in a MV4-11 AML mice CDX model without any body weight loss. This work highlights the potential of targeting MEF2C-dependent AML by selective oral SIK2/3 inhibitors, which was supported by the generative models.
研究领域:
药理学
·
肿瘤学
·
药物化学
·
血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2023
·
IF 3.7
Heyang Zhang,Yuan Tao,Xin Ding,Yue Wang,Xiaoxue Wang
Acute myeloid leukemia (AML) is a myeloid malignancy with generally high mortality. Although recent advances in AML research have revealed that circRNAs play significant roles in AML progression, our understanding of the leukemogenic mechanism of circRNAs remains very limited. In this study, increased expression of hsa_circ_0013880 was observed in bone marrow mononuclear cells (BMNCs) of AML patients. Overexpression of hsa_circ_0013880 promotes AML cell proliferation and migration and reduces cell apoptosis. Mechanistically, hsa_circ_0013880 could elevate the expression of USP32, a deubiquitinating enzyme that is highly expressed in the BMNCs of AML patients. Given the deubiquitination function of USP32, we further hypothesize that USP32 may mediate the malignant behaviors of AML cells by regulating the stability of Ras-related protein (Rap1b). At the molecular level, we find that silencing of USP32 increases ubiquitinated Rap1b. Overexpression of Rap1b restores the effects of USP32 knockdown, which further verifies our hypothesis. In addition, we propose another hypothesis that a potential regulatory network among hsa_circ_0013880, miR-148a-3p/miR-20a-5p and USP32 might exist in the development of AML, according to bioinformatics website predictions and our preliminary experimental verification. Overall, our findings will enrich the understanding of the hsa_circ_0013880/USP32/Rap1b axis in AML development, which may contribute to the development of novel therapeutic strategies for AML.
研究领域:
肿瘤学
·
分子生物学
·
血液学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Cell International
·
2021
·Vol. 21
·期 1
·1-9
·
IF 5.722
Li Li,Zhao Weidong
Background Non-coding RNAs (ncRNAs) have been identified as key regulators during the pathogenesis and development of cancers. However, most of ncRNAs have never been explored in acute myeloid leukemia (AML).Methods Gene expression was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Functional assays were performed to assess the cellular processes in AML cells. The relationship between genes was verified by means of a series of mechanism assays.Results Transmembrane phosphatase with tensin homology pseudogene 1 (TPTEP1) was notably downregulated in AML cells, and functionally acted as a proliferation-inhibitor. Additionally, TPTEP1 suppressed AML cell growth by inactivating c-Jun N-terminal kinase (JNK)/c-JUN signaling pathway. MicroRNA (MiR)-1303, as an oncogene, was predicted and validated as a target of c-JUN in AML cells. Also, TPTEP1 interacted with miR-1303 and they were mutually silenced by each other in AML cells. Furthermore, the effect of TPTEP1 overexpression on AML cell proliferation was counteracted under miR-1303 upregulation.Conclusion Our findings unmasked a feedback loop of TPTEP1/JNK/c-JUN/miR-1303 axis in AML cells, suggesting TPTEP1 and miR-1303 as potential targets for developing therapeutic strategies for AML patients.
研究领域:
分子生物学
·
癌症研究
·
血液学
✓ 已验证
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2024
·
IF 8.5
Yi-Long Ma,Zhi Li,Zheng-Fang Wu,Qian-Lan Wu,Xin Guo,Ya-Fang Shang,Kiran Thakur,Zhao-Jun Wei
The main bioavailable phenolics from of Gongju (GJ) and their mechanism for hepato-protection remain unclear. To select the GJ phenolics with high bioavailability, chrysanthemum digestion and Caco-2 cells were used and their hepato-protective potential were examined by using AML-12 cells. The digestive recovery and small intestinal transit rate of the main phenolic compounds ranged from 28.52 to 69.53% and 6.57% ∼ 15.50%, respectively. Among them, chlorogenic acid , 3,5-dicaffeoylquinic acid, and 1,5-dicaffeoylquinic acid, showed higher small intestinal transit rates and digestive recoveries. Furthermore, we found that by increasing intracellular Catalase (CAT) and Superoxide dismutase (SOD) viability and lowering Malondialdehyde (MDA) level ( P < 0.05 ), 3,5-dicaffeoylquinic acid significantly mitigated the oxidative damage of AML-12 liver cells more than the other two phenolics. Our results demonstrated that 3,5-dicaffeoylquninic acid was the primary phenolic compounds in GJ that effectively reduced liver damage, providing a theoretical basis for the development of GJ as a potentially useful resource for hepatoprotective diet.
研究领域:
营养学
·
药理学
·
食品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Marine Drugs
·
2026
·Vol. 24
·期 2
·
IF 5.7
Xiang Chen,Liting Zhang,Jinqi Huang,Mingzhi Su,Yuewei Guo,Xin Jin
Phorbazoles are bioactive marine alkaloids whose development is hampered by limited supply. We report a concise synthesis of the deschloro-phorbazole core via an optimized iodine-catalyzed oxazole annulation (56% yield). This route enabled efficient access to the scaffold and the preparation of analogB1.B1showed nanomolar cytotoxicity (IC50= 0.04 µM) against MV4-11 leukemia cells by inducing G0/G1 arrest (via cyclin D1/CDK6 downregulation) and apoptosis. As a multi-kinase inhibitor,B1also potently inhibited endothelial network formation and migration, demonstrating anti-angiogenic activity. This work provides an efficient synthetic strategy and identifiesB1as a promising dual-function anticancer lead compound.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-17
·
IF 10.2
Wu Xinzhou,Jiao Zhouguang,Zhang Junying,Li Feng,Li Yuhua
Background Currently, high doses of cytarabine arabinoside (Ara-C)-based combined chemotherapy are commonly used in acute myeloid leukemia (AML) therapy, but severe adverse effects and poor suppression effects in leukemia cells limit the clinical therapeutic efficiency of Ara-C-based chemotherapy due to a lack of targeting selectivity. To improve the therapeutic effect of Ara-C in AML, here, since we confirmed that transferrin receptor 1 (TFRC) expression in AML cells was constant, we generated Ara-C@HFn by encapsulating free Ara-C into self-assembled heavy ferritin chain (HFn, the ligand of TFRC) nanocages.Results The analysis of clinically relevant data suggested that the high expression levels of TFRC from AML cells would not decrease significantly after treatment with Ara-C. Ara-C@HFn can be efficiently internalized by leukemia cells, showing stronger cytotoxic effects in vitro and reducing the burden of leukemia in AML mice more effectively in vivo than free Ara-C. Ara-C@HFn treatment showed no acute toxicity in visceral organs of mice. Moreover, the analysis of clinically relevant data also suggested that there are several drugs (such as tamibarotene and ABT199) that would not cause significant expression down-regulation of TFRC in AML cells (after treatment).Conclusion The above results suggested that TFRC can be used as a constant and effective target for drug targeting delivery of AML cells. Thus Ara-C@HFn treatment can become a safe and efficient strategy for AML therapy by specifically delivering Ara-C to AML cells. Besides, the HFn nanocages are promising for improving antineoplastic effect of other AML-related therapy drugs that do not cause downregulated expression of TFRC in AML cells.Graphical Abstract
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
血液学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 24
·4639-4652
·
IF 6.583
Mengjing Zhao,Huan Zhao,Jiangming Deng,Lianxia Guo,Baojian Wu
Background and Purpose Whether and how circadian clock proteins regulate drug detoxification are not known. Here, we have assessed the effects of CLOCK (a core circadian clock protein) on drug metabolism and detoxification. Experimental Approach Regulation by CLOCK protein of drug-metabolizing enzymes was assessed using Clock knockout ( Clock −/− ) mice and Hepa-1c1c7/AML-12 cells. The relative mRNA and protein levels were determined by qPCR and Western blotting respectively. Toxicity and pharmacokinetic experiments were performed with Clock −/− and wild-type mice after intraperitoneal injection of coumarin or cyclophosphamide. Transcriptional gene regulation was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Key Results Clock deletion disrupted hepatic diurnal expressions of a number of drug-metabolizing enzymes in mice. In particular, CYP2A4/5 expressions were markedly down-regulated, whereas CYP2B10 was up-regulated. Positive regulation of Cyp2a4/5 and negative regulation of Cyp2b10 by CLOCK were confirmed in Hepa-1c1c7 and AML-12 cells. Based on a combination of luciferase reporter, mobility shift, and ChIP assays, we found that CLOCK activated Cyp2a4/5 transcription via specific binding to E-box elements in promoter region and repressed Cyp2b10 transcription through REV-ERBα/β (two target genes of CLOCK and transcriptional repressors of Cyp2b10 ). Furthermore, Clock ablation sensitized mice to coumarin toxicity by down-regulating CYP2A4/5-mediated metabolism (a detoxification pathway) and to cyclophosphamide toxicity by up-regulating CYP2B10-mediated metabolism (generating the toxic metabolite 4-hydroxycyclophosphamide). Conclusion and Implications CLOCK protein regulates metabolism by the cytochrome P450 family and drug detoxification. The findings improve our understanding of the crosstalk between circadian clock and drug detoxification.
研究领域:
药理学
·
分子生物学
·
昼夜节律
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2025
·
IF 4.7
Boying Li,Ran Zhang,Nana Wang,Xiaoning Liu,Ning Li,Jintong Ding,Zhanshuo Cao,Xiongwei Qu,Chengfen Xing
Acute myeloid leukemia (AML) is extremely difficult to cure due to the challenges in accurately targeting it, as it is characterized by rapid progression, high aggressiveness, and high drug resistance. In this study, biomimetic sustained release nanoparticles (PLGA-C-M) were designed and prepared to inhibit the survival and resistance pathways of AML. PLGA-C-M targeted AML cells by wrapping leukemia cell membranes, achieving sustained slow drug release in the blood, and then progressively affecting intracellular Ca2+ signaling by targeting TRPM2 ion channels that were highly expressed in AML in a step-by-step manner. PLGA-C-M can inhibit the growth of AML cells from three aspects: destroying mitochondrial function, reducing autophagy, and overcoming the drug resistance of cancer cells. Biomimetic nanoparticles achieved simultaneous regulation of intracellular ROS and Ca2+ signals to inhibit the growth of leukemia cells and provided ideas for the regulation of ion channel-related signal transduction in AML.
研究领域:
纳米技术
·
癌症生物学
·
药理学
·
生物化学
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
Marine Drugs
·
2024
·Vol. 22
·期 6
·250
·
IF 4.9
Wanting Hao,Leyan Wang,Tongqiang Xu,Geng Jia,Yuqi Jiang,Chong Qin,Xiaoyang Li
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound25cexhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover,25cexhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of25cas a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.
研究领域:
肿瘤学
·
药理学
·
血液学
✓ 已验证
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Lejiao Jia,Huatian Yang,Dandan Zheng,Jingjing Ye,Qian Zhou,Genjv Li,Ying Zhou,Xinyu Yang,Jinting Liu,Feng Ye,Yuliang Song,Daoxin Ma,Chunyan Ji
Acute myeloid leukemia (AML) is rapidly progressed hematologic malignancy with relapsed and refractory characteristics. Cytarabine combined with the BCL2 inhibitor venetoclax showed impressive response rates in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML), while it requires complicated administration regimens and brings added toxicity. In this work, we synthesized a mercaptopropionic acid-substituted derivative of Ara-C (Ara-SH) and used it as the trigger to fabricate a smart cytarabine and venetoclax-coloaded nanoparticle (AV-NP) through self-assembly. The AV-NP characterized with redox-responsive drug release, rapid uptake by leukemia cells, and long retention in circulation had the potential to accumulate in leukemia-enriched sites. It generated a remarkable synergistic effect with higher antileukemia activity in vitro and better safety in the hematologic system compared with free drugs and significantly improved the therapeutic effect on orthotopic AML mice in vivo. These similar results were also confirmed in primary cells from R/R-AML patients. Besides, the AV-NP has the superiority of facile fabrication and generalizability, rendering it easy for clinical translation.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2021
·
IF 7.514
Wen Jing Zhu,Li Ping Lin,Dan Liu,Jia Cheng Qian,Bei Bei Zhou,Dan Dan Yuan,Ren Xiang Tan
Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3′-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.
研究领域:
肿瘤学
·
药理学
·
生物化学
·
发酵科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）