Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase.

We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound .

Engineering the Next Generation of Matched Models for Chemical Translational Biology.

In order to achieve patient personalization and translate compounds through the discovery phase into the clinic, high throughput test models should be designed to be as closely matched to the patient as possible. Engineering high throughput and physiologically relevant biological models is the idealized scenario for testing next generation modulators. I present here a cautionary example of a misaligned model as well as my viewpoint on how overcoming this bottleneck is one of the next frontiers in chemical biology.

Mapping Lipogenic Flux: A Gold LDI-MS Approach for Imaging Neutral Lipid Kinetics.

Spatial characterization of triglyceride metabolism is an area of significant interest which can be enabled by mass spectrometry imaging via recent advances in neutral lipid laser desorption analytical approaches. Here, we extend recent advancements in gold-assisted neutral lipid imaging and demonstrate the potential to map lipid flux in rodents. We address here critical issues surrounding the analytical configuration and interpretation of the data for a group of select triglycerides.

Impact of Extracellular Fatty Acids and Oxygen Tension on Lipid Synthesis and Assembly in Pancreatic Cancer Cells.

Lipid oxidation and biosynthesis are crucial for cell survival, especially for rapidly proliferating cancer cells in a heterogeneous metabolic environment. The storage of high-energy lipid reservoirs competitively advantages the cancer cell over non-neoplastic tissue. Disrupting lipid biosynthetic processes, through modulation of fatty acid (FA) esterification or lipogenesis (DNL), is of interest in drug discovery.

Key Concepts Surrounding Studies of Stable Isotope-Resolved Metabolomics.

"Omics"-based analyses are widely used in numerous areas of research, advances in instrumentation (both hardware and software) allow investigators to collect a wealth of data and therein characterize metabolic systems. Although analyses generally examine differences in absolute or relative (fold-) changes in concentrations, the ability to extract mechanistic insight would benefit from the use of isotopic tracers. Herein, we discuss important concepts that should be considered when stable isotope tracers are used to capture biochemical flux.

Spatial and temporal studies of metabolic activity: contrasting biochemical kinetics in tissues and pathways during fasted and fed states.

The regulation of nutrient homeostasis, i.e., the ability to transition between fasted and fed states, is fundamental in maintaining health.

Characterization of Brain Metabolism by Nuclear Magnetic Resonance.

The noninvasive, quantitative ability of nuclear magnetic resonance (NMR) spectroscopy to characterize small molecule metabolites has long been recognized as a major strength of its application in biology. Numerous techniques exist for characterizing metabolism in living, excised, or extracted tissue, with a particular focus on H-based methods due to the high sensitivity and natural abundance of protons. With the increasing use of high magnetic fields, the utility of in vivo H magnetic resonance spectroscopy (MRS) has markedly improved for measuring specific metabolite concentrations in biological tissues.

Expeditious dissolution dynamic nuclear polarization without glassing agents.

The hyperpolarization of metabolic substrates at low temperature using dynamic nuclear polarization (DNP), followed by rapid dissolution and injection into an MRSI or NMR system, allows in vitro or in vivo observation and tracking of biochemical reactions and metabolites in real time. This article describes an elegant approach to sample preparation which is broadly applicable for the rapid polarization of aqueous small-molecule substrate solutions and obviates the need for glassing agents. We demonstrate its utility for solutions of sodium acetate, pyruvate and butyrate.

Modified murine intracranial aneurysm model: aneurysm formation and rupture by elastase and hypertension.

Introduction: Cerebral aneurysms occur in up to 5% of the population. There are several murine models of aneurysms; however, all have limitations and none reproducibly model aneurysm rupture. To fulfill this need, we modified two current rodent aneurysm models to create a murine model which reproducibly produces intracranial aneurysms and rupture.