ArticleCell chemical biology2019
Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents.
Article in Cell chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05279755 (A Phase 1, Randomized, Double-Blind, Placebo-Controlled Dose Escalating Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending and Multiple Ascending Doses of Prosetin in Healthy Volunteers and Participants With Amyotrophic Lateral Sclerosis), which is not on this map. Cited by 33 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Dose Escalating Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending and Multiple Ascending Doses of Prosetin in Healthy Volunteers and Participants With Amyotrophic Lateral Sclerosis (ALS) With an Optional Open-Label Extended Treatment Period for ALS Participants Who Complete 14 Days of Blinded Treatment
Who cites it
33 citing papers in PubMed.
- The Molecular Machinery of Synaptic Plasticity and Its Potential Role in the Aetiology of Schizophrenia.Molecular neurobiology · 2026Review
- Multinucleation and cytotoxicity induced by multikinase inhibition in highly proliferative cells.Journal of toxicologic pathology · 2026Article
- Targeting MAPK-dependent pathways to modulate reactive astrocyte pathology in neurodegeneration.Communications biology · 2026Article
- A human iPSC-derived sensory neuron platform for high-throughput discovery of neuroprotectants against chemotherapy-induced peripheral neuropathy.Cell reports. Medicine · 2026Article
- Polypharmacology is an enduring and nearly universal property of kinase inhibitors.bioRxiv : the preprint server for biology · 2026Article
- MAP4K signaling pathways in cancer: roles, mechanisms and therapeutic opportunities.Experimental & molecular medicine · 2025Review
- Review
- Mapping multimodal phenotypes to perturbations in cells and tissue with CRISPRmap.Nature biotechnology · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- MAP4 kinase-regulated reduced CLSTN1 expression in medulloblastoma is associated with increased invasiveness.Scientific reports · 2025Article
- Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.Cellular and molecular life sciences : CMLS · 2024Article
- Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.Research square · 2024Article
- Subtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers.Cell chemical biology · 2024Article
- Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.Science advances · 2024Article
- Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.Cell death & disease · 2024Article
- Targeting synapse function and loss for treatment of neurodegenerative diseases.Nature reviews. Drug discovery · 2024Review
- MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice.NPJ Regenerative medicine · 2023Article
- Discovery of a Potent and Selective CDKL5/GSK3 Chemical Probe That Is Neuroprotective.ACS chemical neuroscience · 2023Article
- A Potent and Selective CDKL5/GSK3 Chemical Probe is Neuroprotective.bioRxiv : the preprint server for biology · 2023Article
- Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins.Molecular neurodegeneration · 2023Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Disease-causing mutations in many neurodegenerative disorders lead to proteinopathies that trigger endoplasmic reticulum (ER) stress. However, few therapeutic options exist for patients with these diseases. Using an in vitro screening platform to identify compounds that protect human motor neurons from ER stress-mediated degeneration, we discovered that compounds targeting the mitogen-activated protein kinase kinase kinase kinase (MAP4K) family are neuroprotective. The kinase inhibitor URMC-099 (compound 1) stood out as a promising lead compound for further optimization. We coupled structure-based compound design with functional activity testing in neurons subjected to ER stress to develop a series of analogs with improved MAP4K inhibition and concomitant increases in potency and efficacy. Further structural modifications were performed to enhance the pharmacokinetic profiles of the compound 1 derivatives. Prostetin/12k emerged as an exceptionally potent, metabolically stable, and blood-brain barrier-penetrant compound that is well suited for future testing in animal models of neurodegeneration.
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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.