ABSTRACT
Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR) by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Phenylurea Compounds/pharmacology , Quinolines/pharmacology , Animals , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Gefitinib/pharmacology , Humans , Liver Neoplasms/drug therapy , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Receptors, Fibroblast Growth Factor , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
Nanogels (or nanohydrogels) have been extensively investigated as one of the most promising nanoparticulate biomedical platforms owing to their advantageous properties that combine the characteristics of hydrogel systems with nanoparticles. Among them, smart nanogels that have the ability to respond to external stimuli, such as pH, redox, temperature, enzymes, light, magnetic field and so forth, are most attractive in the area of drug delivery. Besides, numerous multifunctionalized nanogels with high sensitivity and specificity were designed for diagnostic applications. In this feature article, we have reviewed and discussed the recent progress of biodegradable nanogels as smart nanocarriers of anticancer drugs and biomedical diagnostic agents for cancer.
Subject(s)
Drug Carriers/chemistry , Hydrogels/chemistry , Nanoparticles/chemistryABSTRACT
A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 µM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31 µM, SI=48), 3TC (EC50=2.24 µM, SI>39), DDI (EC50=23.20 µM, SI>9) and DLV (EC50=0.65 µM, SI>67), and comparable to AZT (EC50=0.0071 µM, SI>13144) and EFV (EC50=0.0062 µM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Anti-HIV Agents/pharmacology , Binding Sites , Cell Line , Drug Design , Humans , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 µM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 µM. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Drug Design , HIV Reverse Transcriptase/antagonists & inhibitors , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Cell Survival/drug effects , Cells, Cultured , HIV-1/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Nitriles , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured , Virus Replication/drug effectsABSTRACT
A series of CR2(OH)-diarylpyrimidine derivatives (CR2(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC50 values ranging from 7.21±1.99 to 0.067±0.006 µM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC50=0.067±0.006 µM, SI>592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Reverse Transcriptase Inhibitors/chemistry , Binding Sites , Cell Line , HIV Reverse Transcriptase/metabolism , Humans , Molecular Docking Simulation , Protein Structure, Tertiary , Pyrimidines/chemistry , Pyrimidines/metabolism , Reverse Transcriptase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC50 value of 0.26µM and a selectivity index (SI) of 541. The preliminary structure-activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/chemistry , Pyrimidinones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Binding Sites , HIV Reverse Transcriptase/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 µΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.
Subject(s)
Anti-HIV Agents/chemical synthesis , Carboxylic Acids/chemical synthesis , HIV Infections/drug therapy , HIV-1/drug effects , Quinolones/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Carboxylic Acids/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , HIV Infections/pathology , HIV Seropositivity , Humans , Models, Molecular , Quinolones/chemistry , Quinolones/pharmacology , Quinolones/therapeutic use , Structure-Activity RelationshipABSTRACT
A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5 g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC(50) value of 3.17 and 17.88 µM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/metabolism , HIV-1/drug effects , Quinolones/pharmacology , Anti-HIV Agents/chemistry , Cell Line, Transformed , Dose-Response Relationship, Drug , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Glutamine/metabolism , Liver Neoplasms/metabolism , Amino Acid Transport System ASC/antagonists & inhibitors , Animals , Apoptosis/drug effects , Benzeneacetamides/pharmacology , Carrier Proteins/antagonists & inhibitors , Cell Line, Tumor , Drug Synergism , Glutaminase/antagonists & inhibitors , Humans , Mice , Minor Histocompatibility Antigens , Reactive Oxygen Species/metabolism , Thiadiazoles/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the π-π stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.
Subject(s)
Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Hyperthermia, Induced , Indocyanine Green/administration & dosage , Neoplasms/drug therapy , Reactive Oxygen Species/metabolism , Sorafenib/administration & dosage , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Combined Modality Therapy , Drug Synergism , Female , Humans , Indocyanine Green/chemistry , Mice, Inbred BALB C , Mice, Nude , Neoplasms/metabolism , Neoplasms/physiopathology , Neoplasms/therapy , Sorafenib/chemistryABSTRACT
Combination chemotherapy has been proposed to achieve synergistic effect and minimize drug dose for cancer treatment in clinic application. In this article, the stimuli-responsive polymeric nanogels (<100 nm in size) based on poly(acrylic acid) were designed as codelivery system for doxorubicin and cisplatin to overcome drug resistance. By chelation, electrostatic interaction, and π-π stacking interactions, the nanogels could encapsulate doxorubicin and cisplatin with designed ratio and high capacity. Compared with free drugs, the nanogels could deliver more drugs into MCF-7/ADR cells. Significant accumulation in tumor tissues was observed in the biodistribution experiments. The in vitro antitumor studies demonstrated the superior cell-killing activity of the nanogel drug delivery system with a combination index of 0.84, which indicated the great synergistic effect. All the antitumor experimental data revealed that the combination therapy was effective for the multidrug-resistant MCF-7/ADR tumor with reduced side effects.
Subject(s)
Nanoparticles , Cisplatin , Doxorubicin , Drug Delivery Systems , Drug Resistance, Neoplasm , Drug Therapy, Combination , Humans , MCF-7 CellsABSTRACT
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a significant role in anti-HIV drug development. A series of naphthyl-substituted diarylpyrimidines with most EC50 values in the nanomolar range was reported as potent NNRTIs by our lab. In order to obtain the quantitative structure-activity relationship (QSAR) that can guide rational lead optimization, CoMFA and CoMSIA studies were carried out. Docking study based on the co-crystallized complex (PDB ID: 3MEC) was utilized as an approach to obtain reliable conformations for molecular alignment. Two different molecular alignments were performed, resulting in two CoMFA models and 34 CoMSIA models. The CoMSIA models correspond to all the possible combinations among five fields: steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor. Highly predictive models were achieved, in which the statistically reliable CoMFA model had a q(2) of 0.743 and an r(2) of 0.980, whereas the best CoMSIA model had a q(2) of 0.713 and an r(2) of 0.969. The best models were rigorously validated with an external test set, which gave satisfactory predictive r(2) values for CoMFA and CoMSIA models: 0.85 and 0.83, respectively. Contour maps obtained from selected models revealed important structural features and some rational guidance for further optimization.