Integration of MyD88 inhibitor into mesoporous cerium oxide nanozymes-based targeted delivery platform for enhancing treatment of ulcerative colitis.

Excessive reactive oxygen species (ROS) and stressed inflammatory response are major characteristics of ulcerative colitis, which cause disease progression and aggravation. Herein, a novel mesoporous cerium oxide nanozymes (MCN) was designed and then loaded with Myeloid differentiation factor-88 (MyD88) inhibitor for synergistic treatment of colitis by scavenging ROS and regulating inflammation. This innovative MCN with average particle size of 200.7 nm, specific surface area of 119.78 m2/g and mesopores of 4.47 nm not only exhibited excellent SOD-like and CAT-like activities to scavenge ROS but also could act as a carrier to load MyD88 inhibitor, TJ-M2010-5, (abbreviated as TJ-5) into their mesopores, achieving the effect of 'two birds with one stone'. Besides, the modification of dextran sulfate sodium (TJ-5/MCN/DSS) increased the internalization of nanozymes into activated macrophages and enhanced in vitro anti-inflammatory ability. To enhance colon targeting, we coated TJ-5/MCN/DSS with the enteric material Eudragit S100, preventing premature release or absorption of the drug in the gastrointestinal tract after oral administration. The results demonstrated that TJ-5/MCN/DSS/Eudragit not only achieved delayed drug release and improved colon targeting but also exhibited optimal therapeutic efficacy in colitis mice. Mechanistically, the MCN-mediated ROS scavenging and TJ-5-mediated MyD88 blockade synergistically inhibited the NF-κB signaling pathway, thereby reducing the inflammatory response. Importantly, TJ-5/MCN/DSS/Eudragit did not induce systemic toxicity. In conclusion, our work not only presents a novel carrier capable of scavenging ROS but also provides proof of concept for the synergistic treatment of colitis using this carrier in combination with MyD88 inhibitors. This study proposes a safe and efficient strategy for targeting ROS-associated inflammation.

DHW-221, a Dual PI3K/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer.

Multidrug resistance (MDR) is considered as a primary hindrance for paclitaxel failure in non-small cell lung cancer (NSCLC) patients, in which P-glycoprotein (P-gp) is overexpressed and the PI3K/Akt signaling pathway is dysregulated. Previously, we designed and synthesized DHW-221, a dual PI3K/mTOR inhibitor, which exerts a remarkable antitumor potency in NSCLC cells, but its effects and underlying mechanisms in resistant NSCLC cells remain unknown. Here, we reported for the first time that DHW-221 had favorable antiproliferative activity and suppressed cell migration and invasion in A549/Taxol cells in vitro and in vivo. Importantly, DHW-221 acted as a P-gp inhibitor via binding to P-gp, which resulted in decreased P-gp expression and function. A mechanistic study revealed that the DHW-221-induced FOXO3a nuclear translocation via Akt inhibition was involved in mitochondrial apoptosis and G0/G1 cell cycle arrest only in A549/Taxol cells and not in A549 cells. Interestingly, we observed that high-concentration DHW-221 reinforced the pro-paraptotic effect via stimulating endoplasmic reticulum (ER) stress and the mitogen-activated protein kinase (MAPK) pathway. Additionally, intragastrically administrated DHW-221 generated superior potency without obvious toxicity via FOXO3a nuclear translocation in an orthotopic A549/Taxol tumor mouse model. In conclusion, these results demonstrated that DHW-221, as a novel P-gp inhibitor, represents a prospective therapeutic candidate to overcome MDR in Taxol-resistant NSCLC treatment.

Exploration of 4-(1H-indol-3-yl)cyclohex-3-en-1-amine analogues as HDAC inhibitors: Design, synthesis, biological evaluation and modelling studies.

Epigenetics regulate the gene expression and chromatin organization associated with the development and occurrence of cancer. Histone deacetylase inhibitors (HDACis) have been proved to be an effective epigenetic targeting drug for cancer treatment. The structures of most HDACis were divided into four parts, including cap group, connection unit, linker region and zinc binding group. We designed a series of compounds containing the structure of phenoxyacetate for the linker region and cyclohexene for connection unit as a novel type of inhibitors. Representative compound YZ1 exhibited obvious antiproliferative activity against four different cell lines and potent enzymatic inhibitory activities to class I HDACs, which IC50 of HDAC1-3 were 1.6 nM, 1.9 nM and 3.8 nM respectively. In addition, YZ1 concentration-dependently inhibited cell proliferation, induced apoptosis and cycle arrest at G2/M phase in HCT116 cells. With biological activity assessment and docking studies, these results indicate YZ1 has the potential to be a lead compound for further optimization as HDAC inhibitors.

DZW-310, a novel phosphoinositide 3-kinase inhibitor, attenuates the angiogenesis and growth of hepatocellular carcinoma cells via PI3K/AKT/mTOR axis.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide with high lethality and prevalence. The deregulated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an indispensable role in mediating the progression of HCC. Among them, PI3K acts as the most pivotal initiator, contributing to multiple malignant biological processes, like proliferation, apoptosis and angiogenesis. Many PI3K inhibitors (PI3Kis) have been proved or proceeded into clinical as antineoplastic drugs. Nevertheless, the application of PI3Kis for the treatment of HCC remains a blank. Accordingly, our study identified a novel PI3Ki (DZW-310) with strong anti-HCC activity in vitro and in vivo. This study aimed to evaluate its anti-HCC effect and elucidate its potential mechanism. Our current results revealed that DZW-310 significantly attenuated HCC cell growth through promoting intrinsic apoptosis and G0/G1 phase cell arrest. Moreover, DZW-310 suppressed angiogenesis by regulating the HIF-1α/VEGFA axis. Further mechanistic investigation demonstrated that DZW-310, functioned as a PI3Ki, exerted strong anti-HCC activity by acting on PI3Kα (a major subtype of PI3K) and ulteriorly deactivating the PI3K/AKT/mTOR pathway. Collectively, our studies identified that DZW-310 is expected to become a promising HCC therapeutic agent and broaden clinical application of PI3Ki in HCC chemotherapy.

Design, synthesis, and biological evaluation of ß-carboline 1,3,4-oxadiazole based hybrids as HDAC inhibitors with potential antitumor effects.

A series of novel ß-carboline 1,3,4-oxadiazole based hybrids were designed, synthesized, and tested for cytotoxicity and HDAC inhibition. Among the target compounds, compound ZDLT-1 displayed high inhibitory activity for class I HDACs 1, 2, and 3, and potent anti-proliferative activity against HCT116 cells with an IC50 value of 0.173 ± 0.018 µM, it also exhibited better inhibitory activity with an IC50 value of 6 nM for HDAC6 than SAHA (IC50 = 15 nM). Furthermore, the pharmacological experiment of Hoechst staining, colony formation, cell apoptosis assay, and wound healing scratch assay indicated that compound ZDLT-1 was a potent cytotoxic agent against HCT116 cells with cell apoptosis induction. Further, in silico prediction of physicochemical properties, drug-likeness, and ADME parameters suggested that compound ZDLT-1 is a promising anticancer agent. Taken together, the high potency cytotoxicity and class I HDACs inhibitory activity of compound ZDLT-1, which with the ß-carboline 1,3,4-oxadiazole based hybrids as potent anticancer agents could be nominated for further modification and optimization.

ZDQ-0620, a Novel Phosphatidylinositol 3-Kinase Inhibitor, Inhibits Colorectal Carcinoma Cell Proliferation and Suppresses Angiogenesis by Attenuating PI3K/AKT/mTOR Pathway.

The PI3K/AKT pathway plays a central role in human cancers, aberrant activation of this pathway is associated with tumorigenesis, cancer progression and angiogenesis. Based on the importance of the PI3K/AKT pathway in malignancies, we developed a 4-aminoquinazoline derivative, ZDQ-0620, initially envisioned as a novel pan-PI3K inhibitor. This study aimed to evaluate the potential target of ZDQ-0620 and its anticancer effect in human colorectal carcinoma (CRC). PI3K-kinase activity test showed IC50 of ZDQ-0620 against PI3Ka was 0.5 nM; molecular docking, CETSA assay and western blotting was further performed to predict ZDQ-0620 was a PI3K/AKT pathway inhibitor by targeting PI3K. To identify the effect of ZDQ-0620 on CRC cells, Sulforhodamine B (SRB) assay, flow cytometry, and Cell morphology analysis were conducted. The results showed that ZDQ-0620 inhibited the proliferation, migration and invasion of CRC cells, induced apoptosis through G0/G1 cell cycle arrest and mitochondrial pathway. Additionally, ZDQ-0620 inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In vivo, neovascularization of rat aortic ring and chick chorioallantoic membrane (CAM) induced by VEGF was diminished when treated with ZDQ-0620. These results indicate that ZDQ-0620 induce apoptosis and anti-angiogenesis via inhibits the PI3K/AKT pathway. We suggest that the great potential of ZDQ-0620 as an effective treatment candidate against CRC.

Facile synthesis of C1-substituted ß-carbolines as CDK4 inhibitors for the treatment of cancer.

Cyclin-dependent kinase 4 (CDK4), which is involved in dynamic regulation of cell cycle, has gained particularly attention for its role in controlling tumor growth.Increasing evidence showed that ß-carboline derivatives have the potential to inhibit CDK4. Herein, on the basis of previous work, we designed and synthesized a series of novel ß-carbolines and evaluated their antitumor activity.Among them, compounds ZDLD13 and ZDLD20, with the most potent anti-proliferative activity and CDK4 enzymatic inhibition activity, were selected for further pharmacological research in vitro and in vivo. The results in vitro showed that ZDLD13 and ZDLD20 exhibited potent anti-HCT116 activityincluding inhibition of colony formation, inhibition of invasion and migration, inducing of apoptosis, and arresting of G1 phase in cell cycle.In vivo,ZDLD13showed significant tumor growth inhibition in HCT116 tumor xenograft model without causing significant weight loss and toxicityconsistent with the acute toxicity test. In addition, silico study showed ZDLD13 and ZDLD20 not only have good biological actions, but also acceptable predicted ADME and physicochemical properties.Taken together, compoundsZDLD13and ZDLD20 could be selected for further modification and preclinical evaluation.

Zwitterion-Driven Shape Program of Prodrug Nanoassemblies with High Stability, High Tumor Accumulation, and High Antitumor Activity.

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways.

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.

Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3ß/DYRK1A dual inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss and behavioral disturbances, ultimately leading to death. Glycogen synthase kinase 3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation regulated kinase1A (DYRK1A) have gained a lot of attention for its role in tau pathology. To search for potential dual GSK-3ß/DYRK1A inhibitors, we focused on harmine, a natural ß-carboline alkaloid, which has been extensively studied for its various biological effects on the prevention of AD. In this study, a new series of harmine derivatives were designed, synthesized and evaluated as dual GSK-3ß/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3ß and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3ß and DYRK1A with IC50 values of 71 and 103 nM, respectively. Molecular modelling and kinetic studies verified that ZDWX-25 could interact with the ATP binding pocket of GSK-3ß and DYRK1A. Western blot analysis revealed that ZDWX-25 inhibited hyperphosphorylation of tau protein in okadaic acid (OKA)-induced SH-SY5Y cells. In addition, ZDWX-25 showed good blood-brain barrier penetrability in vitro. More importantly, ZDWX-25 could ameliorate the impaired learning and memory in APP/PS1/Tau transgenic mice. These results indicated that the harmine-based compounds could be served as promising dual-targeted candidates for AD.

A computer-aided chem-photodynamic drugs self-delivery system for synergistically enhanced cancer therapy.

The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy, has emerged as a potential development of effective anti-cancer medicine. Nevertheless, co-delivery of photosensitizers (PSs) and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility. Herein, we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a (PPa, a common PS) and podophyllotoxin (PPT, a classical chemotherapeutic drug) for synergistic cancer therapy. First, the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules. Based on the molecular docking, the intermolecular interactions were found to include π-π stackings, hydrophobic interactions and hydrogen bonds. Next, both drugs could co-assemble into nanoparticles (NPs) via one-step nanoprecipitation method. The various spectral experiments (UV, IR and FL) were conducted to evaluate the formation mechanism of spherical NPs. Moreover, in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency, stronger cytotoxicity and higher accumulation in tumor sites, but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice. Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.

Flavonoid-triazolyl hybrids as potential anti-hepatitis C virus agents: Synthesis and biological evaluation.

A series of flavonoid-triazolyl hybrids were synthesized and evaluated as novel inhibitors of hepatitis C virus (HCV). The results of anti-HCV activity assays showed that most of the synthesized derivatives at a concentration of 100 µg/mL inhibited the generation of progeny virus. Among these derivatives, 10m and 10r exhibited the most potent anti-HCV activity and inhibited the production of HCV in a dose-dependent manner. Interestingly, 10m and 10r had no significant inhibitory effect on viral translation or replication. Additional action mechanism studies revealed that the most potent compounds, 10m and 10r, significantly inhibited viral entry to 34.0% and 52.0%, respectively, at 10 µM. These results suggest further effective application of 10m and 10r as potential HCV preventive agents.

Neuroprotective effects of kukoamine A on 6-OHDA-induced Parkinson's model through apoptosis and iron accumulation inhibition.

Objective: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra (SN). Our previous study demonstrated kukoamine A (KuA) to exhibit strong neuroprotective effects through antioxidative stress, and autophagy in MPTP/MPP+-induced PD models in vivo and in vitro. It is necessary to evaluate the efficacy of the anti-PD effects under various models. Methods: In the present study, total chemical synthesis was used to obtain KuA, which performed low content in Lycii Cortex. Then, 6-OHDA-induced PD model of PC12 cells was used to investigate the effects of KuA on PD. Results: Our results demonstrated that KuA ameliorated cell loss and mitochondrial membrane potential (MMP) loss, and inhibited Bax/Bcl-2 ratio increase that were induced by 6-OHDA. Iron accumulation in SN is thought to participate in neuronal death in PD, which subsequently resulted in oxidative stress and overexpression of α-synuclein caused by iron metabolism protein disorder. In our study, KuA could chelate cellular iron content and decrease iron influx. Moreover, KuA could upregulate the expression of ferroportin1 and Hephaestin, downregulate the expression of DMT1, TfR, and Ferritin to maintain cellular iron homeostasis avoiding neuronal death from cellular iron deposition. Moreover, KuA could decrease the expression of a-synuclein in cells. All the results indicated that KuA protected against neurotoxin-induced PD due to the apoptosis inhibition and iron homeostasis maintaining. Conclusion: KuA treatment might represent a neuroprotective treatment for PD.

The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation.

EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC.

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway.

Breast cancer is one of the most frequent cancers among women worldwide. However, there is still no effective therapeutic strategy for advanced breast cancer that has metastasized. Aberrant activation of the PI3K/AKT/mTOR pathway is an essential step for the growth of human breast cancers. In our previous study, we designed and synthesized DHW-208 (2,4-difluoro-N-(5-(4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)quinazolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide) as a novel pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in breast cancer and investigate its underlying mechanism. We found that DHW-208 inhibited the growth, proliferation, migration, and invasion of breast cancer cells. Moreover, DHW-208 induced breast cancer cell apoptosis via the mitochondrial pathway and induced G0/G1 cell-cycle arrest. In vitro results show that DHW-208 is a dual inhibitor of PI3K and mTOR, and suppress the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in breast cancer. Above all, we report for the first time that DHW-208 suppressed the growth of human breast cancer cells by inhibiting the PI3K/AKT/mTOR-signaling pathway both in vivo and in vitro. Our study may provide evidence for the use of DHW-208 as an effective, novel therapeutic candidate for the treatment of human breast cancers in clinical trials.

A comprehensive description of GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonists.

l-glutamate is an excitatory neurotransmitter in the central nervous system (CNS), which can activate ionotropic receptors (iGluRs) and metabotropic (mGluRs) receptors. N-methyl-D-aspartate (NMDA) receptor is a ligand-gated ion channel belonging to the iGluRs family. Among NMDA receptor subtypes, GluN2B subtype plays a crucial role in CNS diseases. In this review, we summarize, classify and discuss the reports on GluN2B antagonists, published from the 1990s to 2020, to provide the therapeutic potential of GluN2B antagonists on various disorders. The GluN2B antagonists are broadly classified into two categories, which are prototypical antagonists and atypical antagonists. And the latter are further divided into amidine derivatives, 4-aminoquinolines, indole derivatives, benzimidazole derivatives, oxamide derivatives, carbamate derivatives, EVT-101 analogues, 1H-pyrrolo[3,2-b]pyridine derivatives, benzazepin derivatives, other heterocyles and radiotracers. This review will provide a comprehensive description including structure, structure-activity relationship (SAR), and pharmacology of novel GluN2B-subtype selective NMDA antagonists to the medicinal chemists, which would be helpful in rational designing effective drugs aimed toward related CNS disease.

Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as anticancer agents.

Phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, autophagy and apoptosis. Class I PI3K is frequently mutated and overexpressed in a lot of human cancers and PI3K was considered as a target for therapeutic treatment of cancer. In this study, we designed and synthesized a series of 1,6-disubstituted-1H-benzo[d]imidazoles derivatives and evaluated their anticancer activity and the compound 8i was identified as a lead compound. Compound 8i with the most potent antiproliferative activity was selected for further biological mechanism. The PI3K kinase assay have shown potent efficiency against four subtypes of PI3K with an IC50 of 0.5-1.9 nM. Molecular docking showed a possible formation of H-bonding with essential amino acid residues. Meanwhile, western blot assay indicated that 8i inhibited cell proliferation via suppression of PI3K kinase activity and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 8i could inhibit the migration and invasion ability of HCT116 cells and could induce apoptosis of HCT116 cells.

Design, synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors.

A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents.

Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer.

Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients.