Project description:The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive.
Project description:Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13 showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer.
Project description:A novel class of quinoxaline-arylfuran derivatives were designed, synthesized, and preliminarily evaluated for their antiproliferative activities in vitro against several cancer cell lines and normal cells. The representative derivative QW12 exerts a potent antiproliferative effect against HeLa cells (IC50 value of 10.58 μM), through inducing apoptosis and triggering ROS generation and the accumulation of HeLa cells in vitro. Western blot analysis showed that QW12 inhibits STAT3 phosphorylation (Y705) in a dose-dependent manner. The BLI experiment directly demonstrated that QW12 binds to the STAT3 recombination protein with a KD value of 67.3 μM. Furthermore, molecular docking investigation showed that QW12 specifically occupies the pY+1 and pY-X subpocket of the SH2 domain, thus blocking the whole transmission signaling process. In general, these findings indicated that the study of new quinoxaline-aryfuran derivatives as inhibitors of STAT3 may lead to new therapeutic medical applications for cancer in the future.
Project description:Sixteen thio/semicarbazide-based benzyloxy derivatives (BT1-BT16) were synthesized and evaluated for their inhibitory activities against monoamine oxidases (MAOs). Most compounds showed better inhibitory activity against MAO-B than against MAO-A. BT1, BT3, and BT5 showed the greatest inhibitory activity with an identical IC50 value of 0.11 µM against MAO-B, followed by BT6 and BT7 (IC50 = 0.12 µM) and BT2 (IC50 = 1.68 µM). The selectivity index of BT5 was the highest (363.64) for MAO-B, whereas that of BT1 was 88.73. BT1 and BT5 were reversible MAO-B inhibitors, based on the results of dialysis experiments. In inhibition kinetics, BT1 and BT5 were competitive MAO-B inhibitors with Ki values of 0.074 ± 0.0020 and 0.072 ± 0.0079 µM, respectively. Additionally, in the in-vitro parallel artificial membrane penetration assay, BT1 and BT5 crossed the blood-brain barrier. Cytotoxicity and possible neuroprotective effects of the lead compounds were assessed using IMR 32 cells. Levels of the antioxidant superoxide dismutase, catalase, and glutathione peroxidase in IMR 32 cells were increased by pretreatment with lead compounds. Five lead molecules (BT1, BT3, BT5, BT6, and BT7) were used for the docking studies. A significant pi-pi interaction with Tyr 326 was observed and molecular dynamics studies were performed for the most promising BT1-MAO-B complex. These results suggested that BT1 and BT5 could be used therapeutically for the treatment of various neurodegenerative diseases.
Project description:To obtain a new anticancer drug, we focused on FER tyrosine kinase. Starting with high-throughput screening with our in-house chemical library, compound 1, which has a pyridine moiety, was found. Referring to their X-ray crystal structure with FES proto-oncogene tyrosine kinase, as a surrogate of FER followed by chemical modification including scaffold hopping of the pyridine template, we discovered pyrido-pyridazinone derivatives with potent FER kinase inhibitory activity. Here, we disclose the structure-activity relationship on the scaffold and representative compound 21 (DS21360717), which showed in vivo antitumor efficacy in a subcutaneous tumor model.
Project description:Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC.
Project description:Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the potential antineoplastic activity of four newly synthesized olivacine derivatives. Multidrug resistance is a common phenomenon causing failure in the chemotherapy of many tumors. It is mainly related to increased function of P-glycoprotein, an efflux pump removing cytostatic out of the cells. The cell lines used in the study were colorectal carcinoma cell lines: LoVo (doxorubicin-sensitive) and LoVo/DX (doxorubicin-resistant). The NHDF cell line was used to assess cell viability. First, the cells were incubated with olivacine derivatives. In the next step, the following assays were performed: DCF-DA assay, MTT assay, rhodamine 123 assay, detection of apoptosis, proliferation inhibition-mitotic index. The tested compounds showed higher antineoplastic potential and lower toxicity than the reference compound ellipticine. The results indicate that the new olivacine derivatives are good candidates for future anticancer drugs.
Project description:Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target. In this study, computational analysis of five thiophene urea-based S6K1 inhibitors was performed. Molecular docking showed that the five compounds formed hydrogen bonds with residues Glu173 and Leu175 of S6K1 and hydrophobic interactions with residues Val105, Leu97 and Met225, and these interactions were key elements for the inhibitory potency of the compounds. Binding free energy (ΔG bind) decomposition analysis showed that Leu97, Glu173, Val 105, Leu175, Leu97 and Met225 contribute the most to ΔG bind. Based on the computer results, phenylpyrazole based amides (D1-D3) were designed and synthesized. Biological evaluation revealed that D2 exhibited 15.9 nM S6K1 inhibition, medium microsomal stability and desirable bioavailability.
Project description:Monoacylglycerol lipase (MAGL) is a key enzyme in the human endocannabinoid system. It is also the main enzyme responsible for the conversion of 2-arachidonoyl glycerol (2-AG) to arachidonic acid (AA), a precursor of prostaglandin synthesis. The inhibition of MAGL activity would be beneficial for the treatment of a wide range of diseases, such as inflammation, neurodegeneration, metabolic disorders and cancer. Here, the author reports the pharmacological evaluation of new disulfiram derivatives as potent inhibitors of MAGL. These analogues displayed high inhibition selectivity over fatty acid amide hydrolase (FAAH), another endocannabinoid-hydrolyzing enzyme. In particular, compound 2i inhibited MAGL in the low micromolar range. However, it did not show any inhibitory activity against FAAH.
Project description:Among the M1 family of oxytocinase aminopeptidases, insulin-regulated aminopeptidase IRAP, is an emerging drug target implicated in various biological pathways and particularly in MHC-I antigen presentation through amino-terminal trimming of exogenous cross-presented peptides. A few series of inhibitors inspired either by angiotensin IV, one of IRAP substrates, or by bestatin a pan aminopeptidase inhibitor, have been disclosed. However, the variety and number of chemotypes remains relatively limited. Here we disclose the design and optimization of a series of hydroxamic acids IRAP inhibitors bearing a 5-substituted indole. Docking studies of the best compound 43 (BDM_92499), a single-digit nanomolar and selective inhibitor of IRAP, suggest an original binding mode and highlight the substituent on the indole and a primary amide as groups driving selectivity. Several inhibitors in the series displayed IRAP-dependent inhibition of antigen cross-presentation. These results pave the way to the development of novel therapeutic agents targeting IRAP.