Glioblastoma (GB), the most aggressive and life-threatening primary brain tumor in adults, poses significant therapeutic challenges. Tumor pyruvate kinase M2 (PKM2) has been implicated in the proliferation and survival of glioma cells. In this study, we designed and synthesized a series of 23 novel tetrazole-based derivatives. The compounds were thoroughly characterized using ¹H, ¹³C, ¹⁹F NMR, along with HRMS analysis. Among them, 1-(imidazo[1,2-a]pyrimidin-3-yl)-2-(5-(naphthalen-2-yl)-2H-tetrazol-2-yl)ethan-1-one (9b) exhibited potent and selective antiproliferative activity against U87MG glioma cells, with minimal effects on bEnd (brain endothelial cell line) non-glioma cells. It emerged as a potent PKM2 inhibitor, with an IC₅₀ of 0.307 µM. Apoptosis assays and cell cycle analysis revealed that compound 9b induced early apoptosis and caused G1 phase arrest. A significant decrease in pyruvate concentration further suggested PKM2 inhibition. In silico studies confirmed the binding affinity to the PKM2 inhibitory site, and RT-PCR data demonstrated its inhibitory activity against PKM2. Additionally, it reduced lactate levels, indicating its potential impact on cellular metabolism. Collectively, these findings suggest that the most potent compound holds promise as a therapeutic candidate against GB.

2024-12-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Hit-to-lead optimization of 4,5-dihydrofuran-3-sulfonyl scaffold against Leishmania amazonensis. Effect of an aliphatic moiety

Article

作者: Vanelle, Patrice ; Santos Urbancg Moncorvo, Fabiana Maia ; Avendaño Leon, Oscar Leonardo ; Kabri, Youssef ; Redon, Sébastien ; Curti, Christophe ; Torres-Santos, Eduardo Caio ; Avendano Leon, Oscar Leonardo

In line with our objective of designing new antileishmanial compounds for oral use, we report the synthesis and biological evaluation in vitro of original 4,5-dihydrofuran derivatives bearing an amidoxime group. Previous optimization focused on position 3 of the dihydrofuran ring involving aromatic fragments, resulting in the identification of the compound (HIT) 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N'-hydroxybenzimidamide (IC₅₀ = 5.4 ± 1.0 μM, L. amazonensis promastigote, IC₅₀ = 7.9 ± 1.1 μM, L. amazonensis intracellular amastigote). In the present work, position 3 was substituted with an aliphatic moiety. This modification was guided by a ligand-based approach, given the unknown biological target or mechanism of action for this compound. The 4,5-dihydrofuran derivatives were synthesized using microwave-assisted manganese (III) acetate-based oxidative cyclization of linear β-keto-carboxylic and β-keto-sulfone substrates, overcoming synthetic challenges to obtain aliphatic derivatives of 4,5-dihydrofuran-3-carboxamides. Finally, an unexpected and interesting biological activity with the 4,5-dihydrofuran-3-carboxylate (IC₅₀ < 5 μM) against the amastigote form is discussed.

2019-01-01·European journal of medicinal chemistry1区 · 医学

First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent

1区 · 医学

Article

作者: Kwon, Youngji ; Choi, Jin Gyu ; Kim, Yun Kyung ; Oh, Myung Sook ; Hassan, Ahmed H E ; Park, Ki Duk ; Roh, Eun Joo ; Farag, Ahmed Karam ; Jeong, Hyeanjeong

Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound 3l, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC₅₀ = 1.25 μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC₅₀ = 5.0 μM). Also, compound 3l elicited potent inhibition of CSF1R in the in vitro kinase assay (IC₅₀ = 0.15 μM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound 3l as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 3l to the substrate-binding site of DAPK1. Hence, compound 3l might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.

项与 APL-030 相关的新闻（医药）

2023-08-29

·MedCity News

Apellis Lays Off 25% of Staff and Turns Focus to Commercializing New Eye Drug

Apellis Pharmaceuticals is laying off about 25% of its staff to find up to $300 million in savings, making it the latest biotech company that is shrinking now to find a way to grow in the future. The corporate shakeup will turn the company’s focus to selling an eye disease drug whose launch earlier this year has been clouded by post-marketing reports of a rare complication. The restructuring announced Tuesday will cut about 225 full time employees. As of the end of 2022, Waltham, Massachusetts-based Apellis reported its headcount was 767. The company said its field-based commercial and medical employees will be minimally affected by the cuts. Those workers will be tasked with the ramping up the commercialization of Syfovre, a drug approved in February for treating the vision-loss disorder geographic atrophy. Syfovre is a peptide drug designed to block C3, a protein of the complement system that’s associated with the excessive immune response contributing to geographic atrophy. In July, reports of a type of eye inflammation called occlusive retinal vasculitis surfaced in a small number of patients who received Syfovre. Apellis later confirmed the adverse effect in seven patients who received the drug, which is administered as an injection into the eye. No such complications were reported in clinical testing of Syfovre, and the company said there were no indications that the manufacturing process contributed to these adverse effects. In an update of its review of the eye complications, Apellis said last week that it identified variations in the 19-gauge filter needle included in certain injection kits. While Apellis said it has not found a causal relationship between this needle and the reported adverse effects, the company is recommending clinicians use kits with the 18-gauge filter needle. In the first half of this year, Apellis reported $85.7 million in Syfovre sales. The company said workers remaining following the restructuring will focus on supporting the U.S. commercial launch of the drug as well as potential launches in other markets. A European Medicines Agency decision is expected early next year. The company has prioritized an initial launch in Germany. The drug is still under review in Canada, Australia, the United Kingdom, and Switzerland. The commercialization push comes as Syfovre faces new competition from Izervay, an Astellas Pharma geographic atrophy drug that won its FDA approval in early August. As Apellis focuses its efforts on marketing Syfovre, it will scale back efforts on its first FDA-approved product, Empaveli. That drug, which contains pegcetacoplan, the same main component of Syfovre, is a treatment for the rare blood disorder paroxysmal nocturnal hemoglobinuria. But Empaveli has not become a big revenue generator for the company. In the first half of 2023, Apellis reported $42.7 million in revenue for that product. The restructuring will reduce the company’s expenses for that drug. Apellis will also shelve two preclinical programs: APL-030 for neurological disorders and APL-2006, a potential treatment for both geographic atrophy and the wet form of age-related macular degeneration. Apellis will continue developing a systemic version of pegcetacoplan for treating immune complex membranoproliferative glomerulonephritis and C3 glomerulopathy, two rare kidney diseases with no approved treatments. A Phase 3 study is underway testing the drug in both diseases. Preliminary data are expected in 2024. But Apellis will not start any new programs with systemic pegcetacoplan. The restructuring is expected to lead to up to $300 million in savings through 2024. In addition to $70 million in savings related to the layoffs, up to $230 million is related to eliminating planned external expenses. The layoffs will lead to a one-time charge of between $9 million and $11 million, which will be incurred mainly in the second half of this year. “These were difficult, but necessary, decisions,” Apellis CEO Cedric Francois said in a prepared statement. “We are thankful for the commitment and contributions of our colleagues who have worked relentlessly to advance life-changing medicines for some of the most challenging diseases patients face.”

上市批准临床3期

100 项与 APL-030 相关的药物交易

登录后查看更多信息