ABHD12 INHIBITORS AND METHODS OF MAKING AND USING SAME
Provided herein are compounds and compositions useful as modulators of ABHD12. Furthermore, the subject compounds and compositions are useful as immunotherapies in treating, for instance, cancer or infectious diseases.
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Paragraph 00119; 00128
(2019/12/04)
Discovery and optimization of selective and in vivo active inhibitors of the lysophosphatidylserine lipase α/β-hydrolase domain-containing 12 (ABHD12)
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.
Ogasawara, Daisuke,Ichu, Taka-Aki,Jing, Hui,Hulce, Jonathan J.,Reed, Alex,Ulanovskaya, Olesya A.,Cravatt, Benjamin F.
p. 1643 - 1656
(2019/02/19)
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