A5073730635- Chemokine receptors and signaling
- Lung Cancer Treatments and Mutations
- Neuropeptides and Animal Physiology
- Peptidase Inhibition and Analysis
- HER2/EGFR in Cancer Research
- Diabetes Treatment and Management
- Gastric Cancer Management and Outcomes
- Multiple Myeloma Research and Treatments
- Cancer therapeutics and mechanisms
- Synthesis and biological activity
- Immune cells in cancer
- Glycosylation and Glycoproteins Research
- Glioma Diagnosis and Treatment
- PI3K/AKT/mTOR signaling in cancer
- Adenosine and Purinergic Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Immunotherapy and Immune Responses
- Cardiac Fibrosis and Remodeling
- Cytokine Signaling Pathways and Interactions
- Signaling Pathways in Disease
- Angiogenesis and VEGF in Cancer
- Phagocytosis and Immune Regulation
- Synthesis and Characterization of Heterocyclic Compounds
- Lung Cancer Research Studies
- 14-3-3 protein interactions
National Health Research Institutes
2011-2023
Czech Academy of Sciences, Institute of Biotechnology
2010
Significance A highly selective, safe, and potent CXCR4 antagonist, BPRCX807, has been designed experimentally validated in various hepatocellular carcinoma models. Through combination therapy, it can synergize with either a kinase (e.g., sorafenib) or checkpoint inhibitor (e.g. anti–PD-1) to augment effectiveness of current anticancer treatments. With its unique mode action, new strategy for preventing cell migration metastasis is provided.
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group obtain potent EGFR kinase inhibitors 11 and 19. Both 19 showed over 3 orders magnitude enhanced HCC827 antiproliferative activity compared also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) at nanomolar concentration. Moreover, treatment with shrinked tumor in nude mice xenograft model.
C-X-C chemokine receptor type 4 (CXCR4) is a for pleiotropic CXCL12. Previous studies have shown that the acute administration of CXCR4 antagonist AMD3100 reduced neuroinflammation in stroke brain and mobilized bone marrow hematopoietic stem cells (HSCs). The purpose this study was to characterize neuroprotective neurotrophic effect novel CX549. We demonstrated CX549 had higher affinity more potent than inhibit CXCL12-mediated chemotaxis culture. effectively activation microglia improved...
The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant was accomplished by replacing the (S)-2-phenylglycinol moiety 12 with either an ethanol or alkyl substituent. Then, cellular potency and physicochemical properties were optimized through insights from molecular modeling studies implanting various solubilizing groups in phenyl rings A B. Optimized lead 52 shows 8-fold selective inhibition H1975...
Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough the field of precision medicine. Previously, we have identified lead compound, furanopyrimidine 2, which contains (S)-2-phenylglycinol structure as key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability its pharmacokinetics studies. In this work, optimized by scaffold hopping exploiting potent inhibitory activity various warhead...
4057 Background: The standard care for advanced gastric adenocarcinoma varies between Western and Asian countries. In patients with HER2-positive cancer, the anti-HER2 antibody trastuzumab recently showed a significant survival benefit in first-line therapy (ASCO 2009). Second-line weekly paclitaxel has shown favorable response rates (14.3-40.0%) cancer is now used widely Japan well accepted other Successful data lapatinib, dual inhibitor of HER2 EGFR, combination have been reported from...
We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4+ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at same dose (6 mg/kg) in mice. This compounds thus provides set valuable tools to study diseases mediated by CXCR4/SDF-1 axis, myocardial infarction, ischemic stroke, cancer metastasis. More importantly, treatment...
Going mobile: Based on screening hit 1, a novel class of polyamine compounds, as represented by compound 8, were identified potent and selective CXCR4 antagonists. CXCR4-targeted molecules, demonstrated the marketed AMD3100 are able to mobilize stem cells from bone marrow effectively expected have broad utility in cell therapy regenerative medicine.
Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications conjunction with vitro neurite outgrowth assay, image-based high-content screening platform, and mouse behavior models, neuroprotective agent CN016 was discovered. Our results showed that could inhibit paclitaxel-induced inflammatory...
The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow peripheral circulation. We have discovered a novel series pyrimidine-based antagonists, representative (i.e., 16) which was tolerated at higher dose showed better HSC-mobilizing ability maximal response relative approved drug 1 (AMD3100),...
Abstract A number of pyrazole compounds reported in literatures elicit anti‐hyperglycemic effects. By modifying the side chain heterocyclic skeleton, a new chemical class DPP‐IV inhibitors structurally derived from (pyrazol‐4‐yl)‐methylamine scaffold have been discovered and evaluated biological activities these against DPP‐IV, DPP8, DPP‐II FAP. The SAR studies showed (1,3‐diphenyl‐1 H ‐pyrazol‐4‐yl)‐methylamines with 2,4‐dichloro substituents at 3‐phenyl ring selectively preferred as...
CXCR4 antagonists have been claimed to reduce mortality after myocardial infarction in (MI) animals, presumably due suppressing inflammatory responses caused by ischemia-reperfusion injury, thus, subsequently facilitating tissue repair and cardiac function recovery. This study aims determine whether a newly designed antagonist DBPR807 could exert better vascular-protective effects than other clinical counterparts (e.g., AMD3100) alleviate damage further exacerbated reperfusion. Consequently,...
e14576 Background: Based on the results of ToGA (Trastuzumab for Gastric Cancer) study, trastuzumab in combination with chemotherapy can be considered as a new standard option patients human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastro-esophageal junction (GEJ) cancer (Lancet 2010;376:687-97). In overall HER2-positivity rate was 22.1%; however, exceptionally low observed some countries, including Taiwan (only 3%; ASCO-GI 2008:A11). The underlying factors...