| Title : Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase alpha\/beta-Hydrolase Domain-Containing 12 (ABHD12) - Ogasawara_2019_J.Med.Chem_62_1643 |
| Author(s) : Ogasawara D , Ichu TA , Jing H , Hulce JJ , Reed A , Ulanovskaya OA , Cravatt BF |
| Ref : Journal of Medicinal Chemistry , 62 :1643 , 2019 |
| Abstract : ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lysophosphatidylserine (lyso-PS) and lysophosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Here, we provide a detailed description of the discovery and activity-based protein profiling (ABPP) guided optimization of reversible thiourea inhibitors of ABHD12 that culminated in the identification of DO264 as a potent, selective, and in vivo active ABHD12 inhibitor. We also show that DO264, but not a structurally related inactive control probe (S)-DO271, augments inflammatory cytokine production from human THP-1 macrophage cells. The in vitro and in vivo properties of DO264 designate this compound as a suitable chemical probe for studying the biological functions of ABHD12-(lyso)-PS/PI pathways. |
| ESTHER : Ogasawara_2019_J.Med.Chem_62_1643 |
| PubMedSearch : Ogasawara_2019_J.Med.Chem_62_1643 |
| PubMedID: 30720278 |
| Gene_locus related to this paper: human-ABHD12 |
| Gene_locus related to this paper: human-ABHD12 |
Ogasawara D, Ichu TA, Jing H, Hulce JJ, Reed A, Ulanovskaya OA, Cravatt BF (2019)
Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase alpha\/beta-Hydrolase Domain-Containing 12 (ABHD12)
Journal of Medicinal Chemistry
62 :1643
Ogasawara D, Ichu TA, Jing H, Hulce JJ, Reed A, Ulanovskaya OA, Cravatt BF (2019)
Journal of Medicinal Chemistry
62 :1643