The lipidome has a broad range of biological and signaling functions, including serving as a structural scaffold for membranes and initiating and resolving inflammation. To investigate the biological activity of phospholipids and their bioactive metabolites, precise analytical techniques are necessary to identify specific lipids and quantify their levels. Simultaneous quantification of a set of lipids can be achieved using high sensitivity mass spectrometry (MS) techniques, whose technological advancements have significantly improved over the last decade. This has unlocked the power of metabolomics/lipidomics allowing the dynamic characterization of metabolic systems. Lipidomics is a subset of metabolomics for multianalyte identification and quantification of endogenous lipids and their metabolites. Lipidomics-based technology has the potential to drive novel biomarker discovery and therapeutic development programs; however, appropriate standards have not been established for the field. Standardization would improve lipidomic analyses and accelerate the development of innovative therapies. This review aims to summarize considerations for lipidomic study designs including instrumentation, sample stabilization, data validation, and data analysis. In addition, this review highlights how lipidomics can be applied to biomarker discovery and drug mechanism dissection in various inflammatory diseases including cardiovascular disease, neurodegeneration, lung disease, and autoimmune disease.

The epidermal growth factor receptor (EGFR) is altered in nearly 60% of glioblastoma (GBM) tumors, however, EGFR tyrosine kinase inhibitors (TKIs) have failed to improve outcomes for GBM patients. This can be attributed to the inability of conventional EGFR TKIs (e.g., erlotinib, gefitinib, lapatinib, afatinib) to effectively cross the blood-brain-barrier (BBB) and reach adequate pharmacological levels for a tumor response. For example, less than 10% of plasma drug concentrations are achieved in the brain for all FDA approved EGFR TKIs. Herein, we performed a structure-activity relationship (SAR) from the 4-anilinoquinazoline scaffold to improve brain penetrance by modifications of physiochemical properties amenable to BBB penetration. Our synthesis scheme aimed to develop EGFR TKIs with low molecular weight and polar surface area, few rotatable bonds and hydrogen bond donors and acceptors, while having high lipophilicity. This yielded novel EGFR TKIs with nanomolar potency against EGFR mutant, GBM patient-derived cells in culture, high BBB penetration (200% brain to plasma), and efficacy against patient-derived orthotopic GBM xenografts. Current efforts are aimed at improving metabolic stability and bioavailability to obtain a clinical EGFR TKI drug candidate for the treatment of GBM.