[Show abstract][Hide abstract] ABSTRACT: Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.
[Show abstract][Hide abstract] ABSTRACT: Cancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) confer a neomorphic enzymatic activity: the reduction of alpha-ketoglutarate (αKG) to D-2-hydroxyglutaric acid (2HG), which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. While selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well-understood. A high-throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified Compound 1, a bis-imidazole phenol that inhibits 2HG production in cells. We investigated the mode of inhibition of Compound 1 and a previously published IDH1 mutant inhibitor with a different chemical scaffold. Steady-state kinetics and biophysical studies show that both of these compounds selectively inhibit mutant IDH1 by binding to an allosteric site, and that inhibition is competitive with respect to Mg(2+). A crystal structure of Compound 1 complexed with R132H IDH1 indicates that the inhibitor binds at the dimer interface and makes a direct contact with a residue involved in binding of the catalytically essential divalent cation. These results show that targeting a divalent cation binding residue can enable selective inhibition of mutant IDH1, and suggest that differences in magnesium binding between wild-type and mutant enzymes may contribute to the inhibitors' selectivity for the mutant enzyme.
[Show abstract][Hide abstract] ABSTRACT: Post-chemotherapy relapse presents a major unmet medical need in AML where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Herein we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten half-life of MYC to achieve substantial growth inhibition of high CD25 expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Since the presence of a CD25 positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
Endocannabinoids (eCBs) play a key neuromodulatory role in the central nervous system, regulating appetite, cognition, emotion, mood and pain by activation of cannabinoid (CB1) receptors. Here we report the pharmacological profile of a potent and selective serine hydrolase monoacylglycerol lipase (MAGL) inhibitor, SAR127303.
Selective pharmacological or genetic blockade of 2-AG hydrolysis affects memory performance and epileptogenesis process.
52nd Annual Meeting of the American College of Neuropsychopharmacology (ACNP) 2013; 01/2014
[Show abstract][Hide abstract] ABSTRACT: PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase
substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and
potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer
target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified
an array of potential novel substrates through orthogonal proteomics approaches. The ensuing effort in structural biology
unveiled for the first time unique features of PRP4 kinase domain and its potential mode of interaction with a low molecular
weight inhibitor. These results provide new and important information for further exploration of PRP4 kinase function in cancer.