21 results on '"Ji, M."'
Search Results
2. New p-Methylsulfonamido Phenylethylamine Analogues as Class III Antiarrhythmic Agents: Design, Synthesis, Biological Assay, and 3D-QSAR Analysis
- Author
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Liu, H., Ji, M., Luo, X., Shen, J., Huang, X., Hua, W., Jiang, H., and Chen, K.
- Abstract
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Using dofetilide (
2 ) as a template of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido phenylethylamine analogues (4a −d and5a −l ). Pharmacological assay indicated that all of these compounds showed activity for increasing the ERP in isolated animal atrium; among them, the effective concentration of compound4a is 1.6 × 10-8 mol/L in increasing ERP by 10 ms, slightly less potent than that of2 , 1.1 × 10-8 mol/L. Compound4a also produced a slightly lower change in ERP at 10-5 M, ΔERP% = 17.5% (ΔERP% = 24.0% for dofetilide). On the basis of this bioassay result, these 16 compounds together with dofetilide were investigated by the three-dimensional quantitative structure−activity relationship (3D-QSAR) techniques of comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another 11 compounds (4e −h and5m −s ) that we synthesized later. Results revealed that the CoMFA, CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have a good correlation with their experimental value, r2 = 0.943, 0.891, and 0.809 for the three QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition forces of the receptor site. On the basis of these results, we designed and synthesized another eight new analogues of methanesulfonamido phenylethyamine (6a −h ) according to the clues provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective concentrations of delaying the ERP by 10 ms of these newly designed compounds correlated well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying ERP at 10-5 M compound6c is much higher than that of dofetilide; the effective concentration of compound6c is 5.0 × 10-8mol/L in increasing the ERP by 10 ms, which is slightly lower than that of2 . The results showed that the 3D-QSAR models are reliable and can be extended to design new antiarrhythmic agents.- Published
- 2002
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3. Design, Synthesis, and Bioevaluation of Novel Reversibly Photoswitchable PI3K Inhibitors Based on Phenylazopyridine Derivatives toward Light-Controlled Cancer Treatment.
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Zhang Y, Deng J, Tian H, Qi H, Xiong T, Lin S, Dong Y, Luo L, Wu D, Zhang K, Ji M, Du T, Sheng L, Chen X, and Xu H
- Subjects
- Humans, Animals, Mice, Phosphatidylinositol 3-Kinases metabolism, Molecular Docking Simulation, Mice, Nude, Zebrafish metabolism, Phosphoinositide-3 Kinase Inhibitors pharmacology, Structure-Activity Relationship, Cell Proliferation, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Neoplasms
- Abstract
Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans - and cis -configuration under irradiation with proper wavelengths. Molecular docking studies show the cis -isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS
365 ( cis -isomer enriched) was more potent than that in the PSSdark ( trans -isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis -isomer, the trans -isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.- Published
- 2024
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4. Discovery of Quinazoline-2,4(1 H ,3 H )-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.
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Zhou J, Du T, Wang X, Yao H, Deng J, Li Y, Chen X, Sheng L, Ji M, and Xu B
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- Male, Humans, Quinazolines pharmacology, X-Rays, Structure-Activity Relationship, Cell Line, Tumor, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use
- Abstract
PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N -substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC
50 = 0.94 nM) and PARP-2 (IC50 = 0.87 nM) but also toward PARP-7 (IC50 = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.- Published
- 2023
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5. Discovery, Optimization, and Evaluation of Novel N -(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment.
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Wang R, Du TT, Liu WQ, Liu YC, Yang YD, Hu JP, Ji M, Yang BB, Li L, and Chen XG
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- Humans, Amines, Interleukin-6, src Homology Domains, Apoptosis, STAT3 Transcription Factor, Neoplasms
- Abstract
Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N -(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12 , compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC
50 value = 2.97 μM) and MDA-MB-231 (IC50 value = 3.26 μM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.- Published
- 2023
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6. Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC.
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Dong H, Ye X, Zhu Y, Shen H, Shen H, Chen W, Ji M, Zheng M, Wang K, Cai Z, Sun H, Xiao Y, and Yang P
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- Humans, ErbB Receptors metabolism, Mutation, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Drug Resistance, Neoplasm, Cell Line, Tumor, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
- Abstract
Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFR
L858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.- Published
- 2023
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7. Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.
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Yuan K, Shen H, Zheng M, Xia F, Li Q, Chen W, Ji M, Yang H, Zhuang X, Cai Z, Min W, Wang X, Xiao Y, and Yang P
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- Humans, Male, Solubility, Prostatic Neoplasms drug therapy
- Abstract
Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC
50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.- Published
- 2023
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8. Characterization of Chlorogenic Acid as a Two-Photon Fluorogenic Probe that Regulates Glycolysis in Tumor Cells under Hypoxia.
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Wang Q, Zhang Q, Zhang Z, Ji M, Du T, Jin J, Jiang JD, Chen X, and Hu HY
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- Humans, Reactive Oxygen Species metabolism, Glycolysis, Oxidative Phosphorylation, Hypoxia, Chlorogenic Acid pharmacology, Neoplasms pathology
- Abstract
High levels of steady-state mitochondrial reactive oxygen species (ROS) and glycolysis are hallmarks of cancer. An improved understanding of interactions between tumor energetics and mitochondrial ROS modulation is useful for the development of new anticancer strategies. Here, we show that the natural product chlorogenic acid ( CGA ) specifically scavenged abnormally elevated mitochondrial O
2 •- and exhibited a two-photon fluorescence turn-on response to tumor cells under hypoxia and tumor tissues in vivo . Furthermore, we illustrated that CGA treatment reduced O2 •- levels in cells, hampered activation of AMP-activated protein kinase (AMPK), and shifted metabolism from glycolysis to oxidative phosphorylation (OXPHOS), resulting in inhibition of tumor growth under hypoxia. This study demonstrates an efficient two-photon fluorescent tool for real-time assessment of mitochondrial O2 •- and a clear link between reducing intracellular ROS levels by CGA treatments and regulating metabolism, as well as undeniably helpful insights for the development of new anticancer strategies.- Published
- 2023
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9. Optimization of Benzamide Derivatives as Potent and Orally Active Tubulin Inhibitors Targeting the Colchicine Binding Site.
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Lin S, Du T, Zhang J, Wu D, Tian H, Zhang K, Jiang L, Lu D, Sheng L, Li Y, Ji M, Chen X, and Xu H
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- Humans, Colchicine metabolism, Tubulin metabolism, Cell Line, Tumor, Binding Sites, Structure-Activity Relationship, Cell Proliferation, Drug Screening Assays, Antitumor, Tubulin Modulators pharmacology, Tubulin Modulators therapeutic use, Tubulin Modulators chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemistry
- Abstract
Targeting the colchicine binding site on tubulin is a promising strategy to develop cancer therapeutics. Herein, we describe our systematic structure-activity relationship studies of benzamide derivatives that lead to an identification of a potent and orally active tubulin inhibitor 48 , which occupied all three zones of the colchicine binding site in the X-ray co-crystal structure, inhibited tubulin polymerization, promoted mitotic blockade and apoptosis, and exhibited significant antiproliferative activities against various cancer cell lines. Compound 48 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacies, and acceptable safety profiles. Furthermore, 48 overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, 48 has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.
- Published
- 2022
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10. Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer.
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Chen W, Ji M, Cheng H, Zheng M, Xia F, Min W, Yang H, Wang X, Wang L, Cao L, Yuan K, and Yang P
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- Female, Humans, Cyclin-Dependent Kinase 4, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors chemistry, Cyclin-Dependent Kinase 6, Breast Neoplasms drug therapy, Breast Neoplasms pathology
- Abstract
Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42 , which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD
50 > 5,000 mg/kg), favorable pharmacokinetic properties ( F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.- Published
- 2022
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11. Correction to "Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia".
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Yuan K, Ji M, Xie S, Qiu Z, Chen W, Min W, Xia F, Zheng M, Wang X, Li J, Hou Y, Kuang W, Wang L, Gu W, Li Z, and Yang P
- Published
- 2022
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12. Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia.
- Author
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Yuan K, Ji M, Xie S, Qiu Z, Chen W, Min W, Xia F, Zheng M, Wang X, Li J, Hou Y, Kuang W, Wang L, Gu W, Li Z, and Yang P
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Cell Proliferation drug effects, Drug Discovery, Female, High-Throughput Screening Assays, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Substrate Specificity, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors
- Abstract
Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in cancer treatment due to the complex and diverse pathogenesis of cancer, and the combination of the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 inhibitor 51 , which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo . In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.
- Published
- 2022
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13. Discovery of Benzocyclic Sulfone Derivatives as Potent CXCR2 Antagonists for Cancer Immunotherapy.
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Dong Y, Fu R, Chen J, Zhang K, Ji M, Wang M, Jiang H, Ye W, Hu J, Li Y, Jin J, Chen X, and Xu H
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- Antineoplastic Agents chemistry, Humans, Immunosuppressive Agents chemistry, Immunotherapy, Sulfones chemistry, Tumor Microenvironment, Antineoplastic Agents pharmacology, Immunosuppression Therapy, Immunosuppressive Agents pharmacology, Neoplasms drug therapy, Receptors, Interleukin-8B antagonists & inhibitors, Sulfones pharmacology
- Abstract
Increasing evidence shows that the CXC chemokine receptor 2 (CXCR2) signaling pathway is essentially implicated in the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and leads to MDSC-mediated immune suppression. Therefore, CXCR2 has recently emerged as a promising drug target for cancer immunotherapy. In this paper, benzocyclic sulfone derivatives were designed as potent CXCR2 antagonists. Structure-activity relationship studies resulted in two lead compounds 9b and 11h , which demonstrated double-digit nanomolar potencies against CXCR2 and significantly inhibited neutrophil infiltration into the air pouch in an in vivo setting. More importantly, 9b and 11h dose-dependently inhibited the tumor growth through oral administration in the Pan02 mouse model. Further cytometry and immunohistochemical analyses revealed that 9b and 11h could reduce the infiltration of neutrophils and MDSCs and enhance the infiltration of CD3
+ T lymphocytes into the Pan02 tumor tissues, shedding light on their mechanisms of action in cancer immunotherapy.- Published
- 2021
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14. Discovery of Quinazoline-2,4(1 H ,3 H )-dione Derivatives Containing 3-Substituted Piperizines as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.
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Zhou J, Ji M, Wang X, Zhao H, Cao R, Jin J, Li Y, Chen X, Sheng L, Chen X, and Xu B
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- Animals, Antineoplastic Agents blood, Antineoplastic Agents chemistry, Crystallography, X-Ray, Dogs, Humans, Mice, Molecular Structure, Poly(ADP-ribose) Polymerase Inhibitors blood, Poly(ADP-ribose) Polymerase Inhibitors chemistry, Poly(ADP-ribose) Polymerases, Quinazolines pharmacology, Rats, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Discovery, Piperazines chemistry, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Quinazolines chemistry
- Abstract
Inhibiting PARP-1/2 offered an important arsenal for cancer treatments via interfering with DNA repair of cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24 , PARP-1: IC
50 = 0.51 nM, PARP-2: IC50 = 23.11 nM; compound 32 , PARP-1: IC50 = 1.31 nM, PARP-2: IC50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.- Published
- 2021
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15. Design, Synthesis, and Biological Evaluation of a Novel Photocaged PI3K Inhibitor toward Precise Cancer Treatment.
- Author
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Zhang K, Ji M, Lin S, Peng S, Zhang Z, Zhang M, Zhang J, Zhang Y, Wu D, Tian H, Chen X, and Xu H
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- Animals, Binding Sites, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation radiation effects, Dogs, Drug Stability, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes metabolism, Molecular Dynamics Simulation, Neoplasms drug therapy, Phosphatidylinositol 3-Kinases chemistry, Phosphoinositide-3 Kinase Inhibitors metabolism, Phosphoinositide-3 Kinase Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors therapeutic use, Pyrimidines chemistry, Pyrimidines metabolism, Pyrimidines pharmacology, Pyrimidines therapeutic use, Rats, Signal Transduction drug effects, Ultraviolet Rays, Xenograft Model Antitumor Assays, Zebrafish metabolism, Drug Design, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors chemical synthesis
- Abstract
Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1 , which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2 . Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.
- Published
- 2021
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16. Discovery of 4-Methylquinazoline Based PI3K Inhibitors for the Potential Treatment of Idiopathic Pulmonary Fibrosis.
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Lin S, Jin J, Liu Y, Tian H, Zhang Y, Fu R, Zhang J, Wang M, Du T, Ji M, Wu D, Zhang K, Sheng L, Li Y, Chen X, and Xu H
- Subjects
- Animals, Bleomycin toxicity, Cell Line, Cell Proliferation drug effects, Crystallography, X-Ray, Drug Evaluation, Preclinical, Half-Life, Humans, Idiopathic Pulmonary Fibrosis chemically induced, Idiopathic Pulmonary Fibrosis drug therapy, Idiopathic Pulmonary Fibrosis pathology, Isoenzymes antagonists & inhibitors, Isoenzymes metabolism, Lung metabolism, Mice, Mice, Inbred ICR, Molecular Conformation, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors metabolism, Phosphoinositide-3 Kinase Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors therapeutic use, Phosphorylation drug effects, Quinazolines metabolism, Quinazolines pharmacology, Quinazolines therapeutic use, Signal Transduction drug effects, Structure-Activity Relationship, Phosphatidylinositol 3-Kinases chemistry, Phosphoinositide-3 Kinase Inhibitors chemistry, Quinazolines chemistry
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.
- Published
- 2019
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17. Discovery of N -Substituted 3-Amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic Acids as Highly Potent Third-Generation Inhibitors of Human Arginase I and II.
- Author
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Van Zandt MC, Jagdmann GE, Whitehouse DL, Ji M, Savoy J, Potapova O, Cousido-Siah A, Mitschler A, Howard EI, Pyle AM, and Podjarny AD
- Subjects
- Arginase metabolism, Crystallography, X-Ray, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Pyrrolidines chemical synthesis, Pyrrolidines chemistry, Structure-Activity Relationship, Arginase antagonists & inhibitors, Drug Discovery, Enzyme Inhibitors pharmacology, Pyrrolidines pharmacology
- Abstract
Recent efforts to identify new highly potent arginase inhibitors have resulted in the discovery of a novel family of (3 R ,4 S )-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid analogues with up to a 1000-fold increase in potency relative to the current standards, 2-amino-6-boronohexanoic acid (ABH) and N -hydroxy-nor-l-arginine (nor-NOHA). The lead candidate, with an N -2-amino-3-phenylpropyl substituent (NED-3238), example 43 , inhibits arginase I and II with IC
50 values of 1.3 and 8.1 nM, respectively. Herein, we report the design, synthesis, and structure-activity relationships for this novel series of inhibitors, along with X-ray crystallographic data for selected examples bound to human arginase II.- Published
- 2019
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18. Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases.
- Author
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Zhang K, Lai F, Lin S, Ji M, Zhang J, Zhang Y, Jin J, Fu R, Wu D, Tian H, Xue N, Sheng L, Zou X, Li Y, Chen X, and Xu H
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor methods, HCT116 Cells, Hep G2 Cells, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors pharmacology, Humans, K562 Cells, MCF-7 Cells, Mice, Mice, Inbred ICR, Molecular Docking Simulation methods, Phosphoinositide-3 Kinase Inhibitors chemical synthesis, Phosphoinositide-3 Kinase Inhibitors pharmacology, Antineoplastic Agents metabolism, Drug Delivery Systems methods, Histone Deacetylase Inhibitors metabolism, Histone Deacetylases metabolism, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors metabolism
- Abstract
Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
- Published
- 2019
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19. Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle.
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Mackman RL, Steadman VA, Dean DK, Jansa P, Poullennec KG, Appleby T, Austin C, Blakemore CA, Cai R, Cannizzaro C, Chin G, Chiva JC, Dunbar NA, Fliri H, Highton AJ, Hui H, Ji M, Jin H, Karki K, Keats AJ, Lazarides L, Lee YJ, Liclican A, Mish M, Murray B, Pettit SB, Pyun P, Sangi M, Santos R, Sanvoisin J, Schmitz U, Schrier A, Siegel D, Sperandio D, Stepan G, Tian Y, Watt GM, Yang H, and Schultz BE
- Subjects
- Administration, Oral, Antiviral Agents administration & dosage, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Biological Availability, Cell Line, Cyclophilins chemistry, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, Hepacivirus drug effects, Lactones administration & dosage, Lactones chemistry, Lactones pharmacokinetics, Lactones pharmacology, Models, Molecular, Protein Conformation, Spiro Compounds administration & dosage, Spiro Compounds chemistry, Spiro Compounds pharmacokinetics, Spiro Compounds pharmacology, Cyclophilins antagonists & inhibitors, Drug Design, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology
- Abstract
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( K
d = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.- Published
- 2018
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20. Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment.
- Author
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Lin S, Wang C, Ji M, Wu D, Lv Y, Zhang K, Dong Y, Jin J, Chen J, Zhang J, Sheng L, Li Y, Chen X, and Xu H
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases chemistry, Phosphatidylinositol 3-Kinases metabolism, Protein Conformation, Quinazolines metabolism, Signal Transduction drug effects, Structure-Activity Relationship, Drug Design, Phosphoinositide-3 Kinase Inhibitors, Quinazolines chemistry, Quinazolines pharmacology
- Abstract
Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.
- Published
- 2018
- Full Text
- View/download PDF
21. Highly potent HCV NS4B inhibitors with activity against multiple genotypes.
- Author
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Phillips B, Cai R, Delaney W, Du Z, Ji M, Jin H, Lee J, Li J, Niedziela-Majka A, Mish M, Pyun HJ, Saugier J, Tirunagari N, Wang J, Yang H, Wu Q, Sheng C, and Zonte C
- Subjects
- Hepacivirus genetics, Magnetic Resonance Spectroscopy, Mass Spectrometry, Genotype, Hepacivirus drug effects, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The exploration of novel inhibitors of the HCV NS4B protein that are based on a 2-oxadiazoloquinoline scaffold is described. Optimization to incorporate activity across genotypes led to a potent new series with broad activity, of which inhibitor 1 displayed the following EC50 values: 1a, 0.08 nM; 1b, 0.10 nM; 2a, 3 nM; 2b, 0.6 nM, 3a, 3.7 nM; 4a, 0.9 nM; 6a, 3.1 nM.
- Published
- 2014
- Full Text
- View/download PDF
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