| Title : Optimization and characterization of a triazole urea inhibitor for alpha\/beta hydrolase domain-containing protein 11 (ABHD11): anti-probe for LYPLA1\/LYPLA2 dual inhibitor ML211 - Adibekian_2011_Probe.Report__1 |
| Author(s) : Adibekian A , Hsu KL , Speers AE , Brown SJ , Spicer T , Fernandez-Vega V , Ferguson J , Cravatt BF , Hodder P , Rosen H |
| Ref : Probe Report , : , 2011 |
| Abstract : Protein palmitoylation is an essential post-translational modification necessary for trafficking and localization of regulatory proteins that play key roles in cell growth and signaling. Multiple oncogenes, including HRAS and SRC, require palmitoylation for malignant transformation. We and others have previously identified lysophospholipase 1 (LYPLA1) as a candidate protein palmitoyl thioesterase responsible for HRAS depalmitoylation in mammalian cells. Seeking chemical tools to investigate biochemical pathway involvement and potential roles in cancer pathogenesis, we conducted a fluorescence polarization-based competitive activity-based protein profiling (FluoPol ABPP) high throughput screening (HTS) campaign to identify inhibitors of LYPLA1 and the structurally related LYPLA2. HTS identified a micromolar triazole urea inhibitor, that we successfully optimized via several rounds of SAR-by-synthesis as ML211 (SID 99445338), a low nanomolar dual inhibitor of LYPLA1 and LYPLA2. The reported probe operates by a covalent mechanism of action and is active both in vitro and in situ. Out of more than 20 serine hydrolases (SHs) profiled by gel-based competitive activity-based protein profiling (ABPP), ML211 was observed to have one anti-target, alpha/beta hydrolase domain-containing protein 11 (ABHD11). Fortuitously, one of the triazole urea library members synthesized during the course of probe optimization was found to be a potent and selective inhibitor of ABHD11, a poorly characterized SH that is hemizygously deleted in Williams-Beuren syndrome [4], and was presented as a control anti-probe (SID 99445332) in the ML211 Probe Report. The optimized ABHD11 probe ML226 is a potent inhibitor of ABHD11, with an IC50 of 15 nM, and exhibits at least 100-fold selectivity for all other SHs (~20) assessed by gel-based competitive ABPP. The probe is also active in situ, completely and selectively inhibiting ABHD11 at sub-nanomolar concentrations. As with ML211, the probe operates by a covalent mechanism of action, carbamoylating the active site serine of ABHD11. The complete properties, characterization, and synthesis of ML226 are detailed in this Probe Report. |
| ESTHER : Adibekian_2011_Probe.Report__1 |
| PubMedSearch : Adibekian_2011_Probe.Report__1 |
| PubMedID: 23658953 |
Adibekian A, Hsu KL, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Cravatt BF, Hodder P, Rosen H (2011)
Optimization and characterization of a triazole urea inhibitor for alpha\/beta hydrolase domain-containing protein 11 (ABHD11): anti-probe for LYPLA1\/LYPLA2 dual inhibitor ML211
Probe Report
:
Adibekian A, Hsu KL, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Cravatt BF, Hodder P, Rosen H (2011)
Probe Report
: