Target Engagement Analysis and Link to Pharmacodynamic Endpoint for a Novel Class of CNS-penetrant and Efficacious p38α MAPK Inhibitors
Open accessAbstract
The protein kinase, p38α MAPK, is a key intracellular transducer of stressor-induced neuroinflammatory responses and, as such, is of high interest as a potential therapeutic target. We recently reported the synthesis and evaluation of first-in-class CNS-penetrant and highly specific p38 MAPK inhibitors that avoid target crossover issues seen in popular small molecule p38 MAPK inhibitors used in hundreds of previous reports. The novel p38 MAPK inhibitors, represented in this study by MW181, are efficacious in vivo. Pharmacodynamic actions include attenuation of stressor-induced increases in brain proinflammatory cytokine levels. We report here more detailed analyses of MW181 target engagement and specific linkage to the downstream increase in glia proinflammatory cytokine production. In vivo validation included demonstration that oral administration of MW181 suppresses lipopolysaccharide-induced increases in mouse brain IL-1β, TNFα, IL-6, IL-10, and CXCL1 but not in a drug-resistant p38α MAPK mutant mouse.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models.
“The p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models [22, 27–33].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [28]
The Introduction explicitly links microglial p38α-mediated cytokine overproduction to inflammation-induced neurotoxicity, citing earlier studies. It also describes protection in a mouse brain-injury model, but does not establish this neurotoxicity link across a variety of mouse models. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The blood-brain barrier: Bottleneck in brain drug development
Pardridge, W. M. (2005) · NeuroRX · doi:10.1602/neurorx.2.1.3 · Cited by 2,798 · see citing works
Mitogen-activated protein kinases in innate immunity
Arthur, J. S. C., & Ley, S. C. (2013) · Nature reviews. Immunology · doi:10.1038/nri3495 · Cited by 1,866 · see citing works
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
Reactive Gliosis and the Multicellular Response to CNS Damage and Disease
Burda, J. E., & Sofroniew, M. V. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.034 · Cited by 1,431 · see citing works
A call for transparent reporting to optimize the predictive value of preclinical research
Landis, S. C., Amara, S. G., Asadullah, K., Austin, C. P., Blumenstein, R., Bradley, E. W., Crystal, R. G., Darnell, R. B., Ferrante, R. J., Fillit, H., et al. (2012) · Nature · doi:10.1038/nature11556 · Cited by 1,196 · see citing works
Microglial dysfunction in brain aging and Alzheimer's disease
Mosher, K. I., & Wyss-Coray, T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.008 · Cited by 618 · see citing works
Chemokines and Chemokine Receptors: Standing at the Crossroads of Immunobiology and Neurobiology
Ransohoff, R. M. (2009) · Immunity · doi:10.1016/j.immuni.2009.09.010 · Cited by 372 · see citing works
Targeting protein kinases in central nervous system disorders
Chico, L. K., Eldik, L. J. V., & Watterson, D. M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2999 · Cited by 292 · see citing works
Self-citationBachstetter, A. D., Xing, B., de Almeida, L., Dimayuga, E. R., Watterson, D. M., & Van Eldik, L. J. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-79 · Cited by 282 · see citing works
Self-citationTong, L., Prieto, G. A., Kramár, E. A., Smith, E. D., Cribbs, D. H., Lynch, G., & Cotman, C. W. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1253-12.2012 · Cited by 254 · see citing works
Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase
Brennan, K. C., Bates, E. A., Shapiro, R. E., Zyuzin, J., Hallows, W. C., Huang, Y., Lee, H.-Y., Jones, C. R., Fu, Y., Charles, A. C., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005784 · Cited by 228 · see citing works
Stewart, B. H., Chan, O. H., Lu, R. H., Reyner, E. L., Schmid, H. L., Hamilton, H. W., Steinbaugh, B. A., & Taylor, M. D. (1995) · Pharmaceutical Research · doi:10.1023/a:1016207525186 · Cited by 186 · see citing works
Park, S.-E., Dantzer, R., Kelley, K. W., & McCusker, R. H. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-12 · Cited by 157 · see citing works
Bachstetter, A. D., & Eldik, L. J. V. (2010) · PubMed Central · Cited by 155 · see citing works
Self-citationEldik, L. J. V., Thompson, W. L., Ranaivo, H. R., Behanna, H. A., & Watterson, D. M. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(07)82015-0 · Cited by 141 · see citing works
Self-citationAccelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies
Shineman, D. W., Basi, G. S., Bizon, J. L., Colton, C. A., Greenberg, B., Hollister, B. A., Lincecum, J. M., Leblanc, G. G., Lee, L. H., Luo, F. R., et al. (2011) · Alzheimer s Research & Therapy · doi:10.1186/alzrt90 · Cited by 137 · see citing works
The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury
Bachstetter, A. D., Rowe, R. K., Kaneko, M., Goulding, D. S., Lifshitz, J., & Eldik, L. J. V. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5399-12.2013 · Cited by 124 · see citing works
Self-citationInhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase
Morfini, G. A., Bosco, D. A., Brown, H. E., Gatto, R. G., Kamińska, A., Song, Y., Molla, L., Baker, L. M., Marangoni, N., Berth, S. H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065235 · Cited by 121 · see citing works
Self-citationXing, B., Bachstetter, A. D., & Van Eldik, L. J. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-84 · Cited by 101 · see citing works
Self-citationChemical Genetics Define the Roles of p38α and p38β in Acute and Chronic Inflammation
O’Keefe, S. J., Mudgett, J. S., Cupo, S. H., Parsons, J. N., Chartrain, N. A., Fitzgerald, C. E., Chen, S.-L., Lowitz, K., Rasa, C. G., Visco, D. M., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704236200 · Cited by 81 · see citing works
Watterson, D. M., Grum-Tokars, V. L., Roy, S. M., Schavocky, J. P., Bradaric, B. D., Bachstetter, A. D., Xing, B., Dimayuga, E., Saeed, F., Zhang, H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066226 · Cited by 80 · see citing works
Self-citationVerkaar, F., van der Doelen, A. A., Smits, J. F. M., Blankesteijn, W. M., & Zaman, G. J. R. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.01.015 · Cited by 41 · see citing works
Shanware, N. P., Williams, L. M., Bowler, M. J., & Tibbetts, R. S. (2009) · BMB Reports · doi:10.5483/bmbrep.2009.42.3.142 · Cited by 39 · see citing works
Xing, B., Bachstetter, A. D., & Eldik, L. J. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056852 · Cited by 17 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Role of p38/MAPKs in Alzheimer's Disease: Implications for Amyloid Beta Toxicity Targeted Therapy
Kheiri, G., Dolatshahi, M., Rahmani, F., & Rezaei, N. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2018-0008 · Cited by 211 · see citing works
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165 · see citing works
Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology
Maphis, N., Jiang, S., Xu, G., Kokiko-Cochran, O. N., Roy, S. M., Van Eldik, L. J., Watterson, D. M., Lamb, B. T., & Bhaskar, K. (2016) · Alzheimer's Research & Therapy · doi:10.1186/s13195-016-0221-y · Cited by 144 · see citing works
Self-citationRoy, S. M., Grum-Tokars, V. L., Schavocky, J. P., Saeed, F., Staniszewski, A., Teich, A. F., Arancio, O., Bachstetter, A. D., Webster, S. J., Van Eldik, L. J., et al. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00002 · Cited by 99 · see citing works
Self-citationAmyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo
Tai, L. M., Koster, K. P., Luo, J., Lee, S., Wang, Y., Collins, N. C., Aissa, M. B., Thatcher, G. R. J., & LaDu, M. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.600833 · Cited by 93 · see citing works
Alam, J. J. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150277 · Cited by 88 · see citing works
Roy, S. M., Minasov, G., Arancio, O., Chico, L. W., Eldik, L. J. V., Anderson, W. F., Pelletier, J. C., & Watterson, D. M. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00058 · Cited by 60 · see citing works
Self-citationRobson, M. J., Quinlan, M. A., Margolis, K. G., Gajewski-Kurdziel, P. A., Veenstra-VanderWeele, J. M., Gershon, M. D., Watterson, D. M., & Blakely, R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1809137115 · Cited by 57 · see citing works
Self-citationPerea, J. R., Ávila, J., & Bolós, M. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.08.007 · Cited by 54 · see citing works
FOXO3–NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function
Thompson, M. G., Larson, M., Vidrine, A. N., Barrios, K., Navarro, F. C., Meyers, K., Simms, P. E., Prajapati, K., Chitsike, L., Hellman, L. M., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501758 · Cited by 54 · see citing works
Bachstetter, A. D., Xing, B., & Eldik, L. J. V. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0175-6 · Cited by 15 · see citing works
Self-citationYu, X.-H., Zhao, Q., Fu, P., Tang, Y.-H., Wang, W.-W., Yu, X.-W., & Ya-Xiong, S. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1790060 · Cited by 1 · see citing works
Umeyor, C. E., Nayak, A., Uronnachi, E., Shah, P., Okeke, T., Okezie, U. M., Bairagi, G., & Patravale, V. B. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23841-3.00020-0
- Authors
- Bachstetter, A. D., Watterson, D. M., & Van Eldik, L. J.
- Affiliations
- University of Kentucky (US)
- Northwestern University (US)
- Venue
- Journal of Neuroimmune Pharmacology
- Published
- 2014-05-01
- Volume
- 9
- Issue
- 4
- Pages
- 454-460
- ISSN
- 1557-1890 (ISSN-L)
- 1557-1904
- PMC
- PMC4122817
- OpenAlex
- W2095596791
- Cited by
- 13
- References
- 24
- Citations by year
- 2026: 1 · 2024: 1 · 2019: 1 · 2018: 3 · 2016: 1 · 2015: 4 · 2014: 2
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Neuroimmune Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- National Institutes of Health
- National Institute on Aging (U01AG043415, R01AG031311, F32AG037280, K99AG044445, AG031311)
- National Institute of Neurological Disorders and Stroke (R01NS064247)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- p38α MAPK inhibitors, target engagement, pharmacodynamics, neuroinflammation, inflammatory cytokines, lipopolysaccharide, IL-1β, TNF-α, interleukin-6, IL-10, CXCL1
- MeSH terms
- Animals, Brain, Cells, Cultured, Dose-Response Relationship, Drug, Drug Resistance, Female, Lipopolysaccharides, Male, Mutation, Neuroglia, Pyridazines, Pyridines, Up-Regulation, Cytokines, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 14, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
