Gliocidin

Gliocidin may be used to investigate its effects on glioblastoma by inhibiting cell proliferation and regulating metabolic pathways. It may also be used to induce tumor cell death in glioblastoma by targeting the de novo purine synthesis pathway through the indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2).

Gliocidin is a potent and low-toxic BBB-permeable prodrug that targets glioblastoma by depleting guanylates via IMPDH2 inhibition; enhances effects with temozolomide. Gliocidin, a nanomolar-potent prodrug (IC50 ~9.17 nM under Nam-depleted conditions), inhibits IMPDH2, disrupting guanine nucleotide synthesis, which is crucial for tumor DNA and RNA production. Activated via the NAD+ salvage pathway into gliocidin-adenine dinucleotide (9-AD), it selectively depletes guanylate in tumor cells, leading to cell death. Gliocidin demonstrates effective blood-brain barrier penetration (brain/plasma ratio ~7.75) and significantly reduces glioblastoma growth in vivo at 50 mg/kg intraperitoneally, twice daily, without observed toxicity. Sensitivity to nicotinamide levels (IC50 increases to 35.7 μM with 1 mM Nam) underscores its pathway dependence. Combined with temozolomide (50 mg/kg/day), gliocidin′s efficacy improves through NMNAT1 upregulation, enhancing 9-AD formation and maintaining a strong safety profile. Gliocidin is known to modulate mTOR complex 1 (mTORC1) signaling and impact purine metabolism.