DO264

DO264 is an inhibitor of α/β-hydrolase domain-containing protein 12 (ABHD12; IC₅₀ = 11 nM).¹ It inhibits ABHD12-dependent hydrolysis of lysophosphatidylserine (lyso-PS) in mouse brain membrane lysates (IC₅₀ = 2.8 nM) and human THP-1 cells.² DO264 increases levels of chemokine (C-C motif) ligand 3 (CCL3), CCL4, TNF-α, and IL-1β in M1-polarized THP-1 macrophages. It potentiates ferroptotic cell death induced by the glutathione peroxidase 4 (GPX4) inhibitor RSL3 in HT1080 fibrosarcoma and SU-DHL-5 B cell lymphoma cells when used at a concentration of 1 μM.^1,3 In vivo, DO264 (30 mg/kg per day for four weeks) increases levels of 1-stearoyl-2-hydroxy-sn-glycero-3-PS, 1-arachidonoyl-2-hydroxy-sn-glycero-3-PS, 1-docosanoyl-2-hydroxy-sn-glycero-3-PS, 1-stearoyl-2-arachidonoyl-sn-glycero-3-PS, and 1-oleoyl-2-arachidonoyl-sn-glycero-3-PS in mouse brain.² It increases levels of CCL2, CCL3, and CCL5 in bronchoalveolar lavage fluid (BALF) and decreases survival in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV) clone 13 when administered at a dose of 30 mg/kg.

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1. Ogasawara, D., Ichu, T.-A., Jing, H., et al. Discovery and optimization of selective and in vivo active inhibitors of the lysophosphatidylserine lipase α/β-hydrolase domain-containing 12 (ABHD12). J. Med. Chem. 62(3), 1643-1656 (2019).

2. Ogasawara, D., Ichu, T.-A., Vartabedian, V.F., et al. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat. Chem. Biol. 14(12), 1099-1108 (2018).

3. Kathman, S.G., Boshart, J., Jing, H., et al. Blockade of the lysophosphatidylserine lipase ABHD12 potentiates ferroptosis in cancer cells. ACS Chem. Biol. 15(4), 871-877 (2020).