Discovery of a novel SHIP1 agonist that promotes degradation of lipid-laden phagocytic cargo by microglia
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Here, we describe the use of artificial intelligence to identify novel agonists of the SH2-containing 5′ inositol phosphatase 1 (SHIP1). One of the compounds, K306, represents the most potent agonist identified to date. We find that K306 exhibits selectivity for SHIP1 vs. the paralog enzyme SHIP2, and this activation does not require the C2 domain of SHIP1 which other known SHIP1 agonists require. Thus, K306 represents a new class of SHIP1 agonists with a novel mode of agonism. Importantly, we find that K306 can suppress induction of inflammatory cytokines and iNOS in macrophages or microglia, but not by their SHIP1-deficient counterparts. K306 also reduces TNF-α production in vivo in an LPS-induced endotoxemia assay. Finally, we show that K306 enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia revealing a novel function for SHIP1 that might be exploited therapeutically in dementia.
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A SHIP1 agonist can enhance phagocytic degradation of synaptosomes and dead neurons by microglia.
“Recent work showed that a SHIP1 agonist can enhance phagocytic degradation of synaptosomes and dead neurons by microglia.64”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [64]
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Chu, Y. N., Akahori, A., Takatori, S., & Tomita, T. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-31978-5_30 · Cited by 3 · see citing works
Vilela, W. R., Platt, N., Bechara, L. R. G., de Paula, G. C., Ferreira, J. C. B., de Oliveira, J., Duarte, J. M. N., & Bem, A. F. D. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05455-7 · Cited by 4 · see citing works
SHIP1 modulation and proteome characterization of microglia
Ahat, E., Shi, Z., Chu, S., Bui, H. H., Mason, E. R., Soni, D. M., Roth, K. D. W., Chalmers, M. J., Oblak, A. L., Zhang, J., et al. (2024) · Journal of Proteomics · doi:10.1016/j.jprot.2024.105198 · Cited by 3 · see citing works
Neuro‐immune interactions in health and disease: Insights from FENS‐Hertie 2022 Winter School
Binder, L. B., da Rosa, P. B., de Sousa, B. M., Chagas, L. D. S., Dubljević, O., Martineau, F. S., Mottarlini, F., Castany, S., Morton, L., Krstanović, F., et al. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16262 · Cited by 2 · see citing works
Structure–Activity Studies on Bis-Sulfonamide SHIP1 Activators
Meyer, S. T., Fernandes, S., Anderson, R. E., Pacherille, A., Toms, B. B., Kerr, W. G., & Chisholm, J. D. (2023) · Molecules · doi:10.3390/molecules28248048 · Cited by 1 · see citing works
Self-citationSHIP1 regulates TREM2 signalling and macrophage functions in a hiPSC-derived modelPreprint
Martin, C., Obst, J., Ibarra, S., Murphy, E. J., Gospodinova, K., & Mead, E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.02.662745
SHIPi improves hematologic recovery after chemotherapy
Fernandes, S., Pedicone, C., Dungan, O. M., Pacherille, A., Meyer, S. T., Dormann, S., del Fresno, C., Sancho, D., Toms, B. B., Walker, B., et al. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01383-3
Self-citationXi, R., Zheng, X., Zhao, J., & Fu, Y. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03819-x · Cited by 1 · see citing works
SHIP1 is required for T cell surveillance of occult malignancies
Fernandes, S., Srivastava, N., Pedicone, C., Sudan, R., Engelman, R. W., & Kerr, W. G. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06326-7
Self-citationSHIP1 regulates TREM2 signalling and macrophage functions in a hiPSC ‐derived model
Martin, K. S., Obst, J., Ibarra, S., Murphy, E. J., Gospodinova, K., & Mead, E. (2026) · FEBS Journal · doi:10.1111/febs.70752
- Authors
- Pedicone, C., Fernandes, S., Matera, A., Meyer, S. T., Loh, S., Ha, J.-H., Bernard, D., Chisholm, J. D., Paolicelli, R. C., & Kerr, W. G.
- Affiliations
- SUNY Upstate Medical University (US)
- University of Lausanne (CH)
- Syracuse University (US)
- Numerion Labs (United States) (US)
- Corresponding author
- Paolicelli, Rosa Chiara
- Kerr, William G.
- ORCID
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 25
- Issue
- 4
- Pages
- 104170
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC9020084
- OpenAlex
- W4220918833
- Cited by
- 26
- References
- 68
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 2
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by-nc-nd)
- IRIS (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (RO1 AG059717)
- ERC
- European Research Council (REMIND 804949)
- Stiftung Synapsis - Alzheimer Forschung Schweiz AFS
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- SHIP1, microglia, neuroinflammation, TNF-α, inducible nitric oxide synthase, endotoxemia, dementia, artificial intelligence in drug discovery
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