ABSTRACT
A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95â¯nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58â¯nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.
Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Design , Imidazoles/pharmacology , Membrane Glycoproteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Receptor, trkB/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Membrane Glycoproteins/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazines/chemical synthesis , Pyrazines/chemistry , Receptor, trkB/metabolism , Structure-Activity Relationship , Wound Healing/drug effectsABSTRACT
Collective data suggest tropomyosin-related kinase B (TrkB), which is correlated with the growth, migration and poor prognosis of neuroblastoma (NB), is a potential target for NB target therapy. Several Phase I/II pan-Trk inhibitors display impressive clinical outcomes but still no drug has been approved for general use. In this paper, we report a novel structural TrkB inhibitor GZD2202, a structural derivative of our previously identified DDR1 antagonists. GZD2202 demonstrates a moderate selectivity between Trk B/C and TrkA. GZD2202 suppresses the brain-derived neurotrophic factor (BDNF) -mediated TrkB signalling pathway, proliferation, migration and invasion in SH-SY5Y-TrkB neuroblastoma cells, and causes about 36.1% growth inhibition in a SH-SY5Y-TrkB neuroblastoma xenograft model.
Subject(s)
Neuroblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptor, trkB/antagonists & inhibitors , Animals , Brain-Derived Neurotrophic Factor/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Male , Mice , Mice, SCID , Neoplasm Invasiveness , Neoplasm Metastasis , Neuroblastoma/pathology , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 proteins with Kd values of 7.9 and 8.0 nM; potently inhibited the kinases with IC50 values of 9.4 and 20.4 nM, respectively; and was significantly less potent for a panel of 403 wild-type kinases at 1.0 µM. DDR1- and DDR2-kinase inhibition by 5n was validated by Western-blotting analysis in primary human lung fibroblasts. The compound also dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release in vitro and exhibited promising in vivo anti-inflammatory effects in an LPS-induced-acute-lung-injury (ALI) mouse model. Compound 5n may serve as a lead compound for new anti-inflammatory drug discovery.
Subject(s)
Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Discoidin Domain Receptor 1/antagonists & inhibitors , Discoidin Domain Receptor 2/antagonists & inhibitors , Drug Design , Pneumonia/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Animals , Humans , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
A series of pyrazolo[1,5-a]pyridine-3-carboxamide hybrids were designed and evaluated as novel anti-tubercular agents. The representative hybrid 7 exhibited promising in vitro activity against susceptive strain H37Rv and a panel of drug-resistant Mtb strains with MIC values of 0.006 µg/mL and ranged from 0.003 to 0.014 µg/mL, respectively. More importantly, the hybrid 7 also showed very low cytotoxicity, and could significantly reduce the mycobacterial burden in a mouse model infected with autoluminescent H37Ra strain, which may serve as a lead compound for further development of new anti-tubercular agents.
