ArticleJournal of medicinal chemistry2013
Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3.
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 87 citations in OpenAlex.
- Mixed lineage kinase 3 contributes to myocardial ischemia/reperfusion injury by regulating neutrophil activation.Basic research in cardiology · 2025Article
- Targeting Bcl-xL with Navitoclax Effectively Eliminates Senescent Tumor Cells That Appear Following CEP-1347-Induced Differentiation of Glioma Stem Cells.International journal of molecular sciences · 2025Article
- Decoding the role of glucocorticoid-regulated kinase 1 in Alzheimer's disease: a promising path toward novel therapeutic strategies.Inflammopharmacology · 2025Review
- AI-DrivenJournal of medicinal chemistry · 2025Article
- Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC.Journal of medicinal chemistry · 2024Article
- Hybrid Amyloid Quantum Dot Nano-Bio Assemblies to Probe Neuroinflammatory Damage.ACS chemical neuroscience · 2024Article
- CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells.International journal of molecular sciences · 2024Article
- Design and synthesis of Meldrum's acid based 7-azaindole anchored 1,2,3-triazole hybrids as anticancer agents.RSC medicinal chemistry · 2024Article
- A novel FGFR1 inhibitor CYY292 suppresses tumor progression, invasion, and metastasis of glioblastoma by inhibiting the Akt/GSK3β/snail signaling axis.Genes & diseases · 2024Article
- TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer.Oncogene · 2023Article
- MLK3 Regulates Inflammatory Response via Activation of AP-1 Pathway in HEK293 and RAW264.7 Cells.International journal of molecular sciences · 2022Article
- URMC-099 prophylaxis prevents hippocampal vascular vulnerability and synaptic damage in an orthopedic model of delirium superimposed on dementia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Membrane repair triggered by cholesterol-dependent cytolysins is activated by mixed lineage kinases and MEK.Science advances · 2022Article
- c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease.Journal of cellular signaling · 2022Article
- The regulatory function of mixed lineage kinase 3 in tumor and host immunity.Pharmacology & therapeutics · 2021Review
- Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer CellsMolecular cancer therapeutics · 2021Article
- Azaindole therapeutic agents.Bioorganic & medicinal chemistry · 2020Article
- Identification of an Antiviral Compound from the Pandemic Response Box that Efficiently Inhibits SARS-CoV-2 Infection In Vitro.Microorganisms · 2020Article
- Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload.Cell death & disease · 2020Article
- Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2020Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.