Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.
Human tissue transglutaminase (hTG2) is a multifunctional enzyme with protein cross-linking and G-protein activity, both of which have been implicated in the progression of diseases such as fibrosis and cancer...
6-alkoxy-2-aminopurine derivatives are potent inhibitors of Cyclin Dependent Kinases (CDKs), with some selectivity towards CDK2 and thus have potential as cancer therapeutics. Development of these inhibitors for targeting CDK2-cyclin A/E...
Preparative thin layer chromatography (prepTLC) is a commonly used method of purification suitable for small scale reactions. However, descriptions of the preferred methodology to load, run, and recover samples from prepTLC are non-standard and varied, making it part of the “hidden curriculum” of laboratory technique. In this article we report on the simple, cost-effective methods we use to load and collect samples from a plate, which enhance the convenience, speed, and precision of this technique.
6-alkoxy-2-aminopurine derivatives are potent inhibitors of Cyclin Dependent Kinases (CDKs), with some selectivity towards CDK2 and thus have potential as cancer therapeutics. Development of these inhibitors for targeting CDK2-cyclin A/E complexes has previously involved a thorough investigation of structure activity relationships of the C 2 amine moiety. However, the established synthesis of these compounds, which uses the alcohol reagent as solvent, limits the complexity of the O 6 functionality which is required for more selective targeting. Herein we report an improved and refocused synthesis of a model CDK2 inhibitor (NU6247), affording convenient access to inhibitors with O 6 substituents whose parent alcohol is not amenable for use as solvent. This revised synthesis allows for a meaningful exploration of the O 6 position in this class of CDK2 inhibitors.
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