High-throughput glycolytic inhibitor discovery targeting glioblastoma by graphite dots–assisted LDI mass spectrometry

Abstract

Malignant tumors will become vulnerable if their uncontrolled biosynthesis and energy consumption engaged in metabolic reprogramming can be cut off. Here, we report finding a glycolytic inhibitor targeting glioblastoma with graphite dots–assisted laser desorption/ionization mass spectrometry as an integrated drug screening and pharmacokinetic platform (GLMSD). We have performed high-throughput virtual screening to narrow an initial library of 240,000 compounds down to the docking of 40 compounds and identified five previously unknown chemical scaffolds as promising hexokinase-2 inhibitors. The best inhibitor (Compd 27) can regulate the reprogrammed metabolic pathway in U87 glioma cells (median inhibitory concentration ~ 11.3 μM) for tumor suppression. Highly effective therapy against glioblastoma has been demonstrated in both subcutaneous and orthotopic brain tumors by synergizing Compd 27 and temozolomide. Our glycolytic inhibitor discovery can inspire personalized medicine targeting reprogrammed metabolisms of malignant tumors. GLMSD enables large, high-quality data for next-generation artificial intelligence–aided drug development.

Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

“…Thus, considerable and continuous efforts are being directed toward exploiting specific dependencies to identify novel molecular targets and design new effective therapeutic strategies that help improve the patient’s clinical care with GBM ( 8 , 35 , 122 ). Indeed, the paradigm of focusing on cancer metabolism was freshly required beyond the dramatic flexibleness of tumor metabolic cascades reported in cancer cells challenged with multiplex inhibitors, including glycolysis and glutaminase inhibitors ( 123 , 124 ).…”

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

“…Multiple state-of-the-art drug design software and molecular docking programs are now available [ 405 , 406 , 407 ], and these can be used in combination with advanced structural prediction algorithms such as AlphaFold to arrive at potential therapeutic compounds, especially for difficult drug targets that lack available structural information [ 408 ]. Another example includes the integrated platform of high-throughput virtual screening and graphite dots–assisted laser desorption/ionization mass spectrometry for drug discovery (GLMSD), allowing for rapid screening and identification of five potent HK2 inhibitors from initial 240,000 compounds [ 409 ].…”

Mass tag-encoded nanointerfaces for multiplexed mass spectrometric analysis and imaging of biomolecules

“…By virtue of multiplex analysis, MS technology has been extensively used and has gained tremendous success in multiomics analyses, 4,5 clinical assays, 6,7 drug screening, 8,9 and microbial identification. 10,11 However, MS characterization of biomolecules with extremely low abundance and high dynamics in biosystems remains challenging.…”