SHIP1-IN-1 is an orally active, blood-brain barrier-permeable SHIP1 ligand. SHIP1-IN-1 exhibits IC50 values of 384 μM and 177 μM against human SHIP1, and an IC50 value of 379 μM against murine SHIP1. SHIP1-IN-1 alters the binding state of SHIP1 to phosphatidylinositol membranes, and regulates phosphoinositide pools and phosphorylated AKT levels. SHIP1-IN-1 enhances the uptake of myelin/membrane fragments and amyloid proteins by microglia, alters gene expression and reduces IL-1β levels. SHIP1-IN-1 can be used in studies related to Alzheimer's disease [1] [2].
In Vivo, SHIP1-IN-1 (compound 32) (150 mg/kg; p.o.; three times at 12-h intervals) achieves brain exposure that alters IL-1β levels, indicating modulation of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease[1].
In Vitro, SHIP1-IN-1 (compound 32) inhibits the human two‑domain SHIP1 protein construct with an IC50 of 384 μM, the human five‑domain SHIP1 protein construct with an IC50 of 177 μM, and the murine five‑domain SHIP1 protein construct with an IC50 of 379 μM[1]. SHIP1-IN-1 (1.0-10 μM) modulates the phosphoinositide association profile of the human five-domain SHIP1 protein, increasing relative binding to PI(3,4)P2 at higher concentrations[1]. SHIP1-IN-1 (60 min treatment at 37 °C; 3 min heating at 44.2 °C) engages full-length SHIP1 in HMC3 cells, reducing protein thermal stability with an AC50 of 40.4 μM[1]. SHIP1-IN-1 (15 min) modulates proximal SHIP1-dependent AKT signaling in IL-4-conditioned THP-1 cells, reducing the pAKT (S473)/tAKT ratio with an IC50 of 4.0 μM and the pAKT (T308)/tAKT ratio with an IC50 of 5.3 μM[1]. SHIP1-IN-1 enhances pHrodo-myelin/membrane debris uptake in both BV2 murine microglia (EC50 = 0.777 μM) and primary murine microglia (EC50 = 0.484 μM), while reducing cell count and nuclear intensity with IC50 values of 3.45 and 6.46 μM in BV2 cells, and 5.65 and 19.4 μM in primary microglia, respectively[1]. SHIP1-IN-1 (50 nM-950 μM; 20 min pre-incubation with enzyme, 10 min reaction with substrate) inhibits purified SHIP1 Ptase-C2 domain activity with an IC50 of 302 μM[2]. SHIP1-IN-1 (Example 9) increases phagocytosis, reduces cell count, and alters nuclear intensity in primary mouse microglia in an in vitro high-content imaging assay[2].
References:
[1]. Jesudason CD, et al. Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models. bioRxiv [Preprint]. 2026 Jan 2:2025.12.31.697127.
[2]. Richardson TI, et al. Crizotinib analogues as ship1 inhibitors useful to treat alzheimer's diseases. WO, WO2024015759A1. 2024-01-18.
In Vivo, SHIP1-IN-1 (compound 32) (150 mg/kg; p.o.; three times at 12-h intervals) achieves brain exposure that alters IL-1β levels, indicating modulation of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease[1].
In Vitro, SHIP1-IN-1 (compound 32) inhibits the human two‑domain SHIP1 protein construct with an IC50 of 384 μM, the human five‑domain SHIP1 protein construct with an IC50 of 177 μM, and the murine five‑domain SHIP1 protein construct with an IC50 of 379 μM[1]. SHIP1-IN-1 (1.0-10 μM) modulates the phosphoinositide association profile of the human five-domain SHIP1 protein, increasing relative binding to PI(3,4)P2 at higher concentrations[1]. SHIP1-IN-1 (60 min treatment at 37 °C; 3 min heating at 44.2 °C) engages full-length SHIP1 in HMC3 cells, reducing protein thermal stability with an AC50 of 40.4 μM[1]. SHIP1-IN-1 (15 min) modulates proximal SHIP1-dependent AKT signaling in IL-4-conditioned THP-1 cells, reducing the pAKT (S473)/tAKT ratio with an IC50 of 4.0 μM and the pAKT (T308)/tAKT ratio with an IC50 of 5.3 μM[1]. SHIP1-IN-1 enhances pHrodo-myelin/membrane debris uptake in both BV2 murine microglia (EC50 = 0.777 μM) and primary murine microglia (EC50 = 0.484 μM), while reducing cell count and nuclear intensity with IC50 values of 3.45 and 6.46 μM in BV2 cells, and 5.65 and 19.4 μM in primary microglia, respectively[1]. SHIP1-IN-1 (50 nM-950 μM; 20 min pre-incubation with enzyme, 10 min reaction with substrate) inhibits purified SHIP1 Ptase-C2 domain activity with an IC50 of 302 μM[2]. SHIP1-IN-1 (Example 9) increases phagocytosis, reduces cell count, and alters nuclear intensity in primary mouse microglia in an in vitro high-content imaging assay[2].
References:
[1]. Jesudason CD, et al. Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models. bioRxiv [Preprint]. 2026 Jan 2:2025.12.31.697127.
[2]. Richardson TI, et al. Crizotinib analogues as ship1 inhibitors useful to treat alzheimer's diseases. WO, WO2024015759A1. 2024-01-18.