A review on potential heterocycles for the treatment of glioblastoma targeting receptor tyrosine kinases

Abstract

Glioblastoma, the most aggressive form of brain tumor, poses significant challenges in terms of treatment success and patient survival. Current treatment modalities for glioblastoma include radiation therapy, surgical intervention, and chemotherapy. Unfortunately, the median survival rate remains dishearteningly low at 12-15 months. One of the major obstacles in treating glioblastoma is the recurrence of tumors, making chemotherapy the primary approach for secondary glioma patients. However, the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms. Consequently, considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs. To tackle glioma, numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEK-ERK-MPAK. By targeting specific signaling pathways, heterocyclic compounds have demonstrated efficacy in glioma therapeutics. Additionally, key kinases including phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase, cytoplasmic tyrosine kinase (CTK), receptor tyrosine kinase (RTK) and lipid kinase (LK) have been considered for investigation. These pathways play crucial roles in drug effectiveness in glioma treatment. Heterocyclic compounds, encompassing pyrimidine, thiazole, quinazoline, imidazole, indole, acridone, triazine, and other derivatives, have shown promising results in targeting these pathways. As part of this review, we propose exploring novel structures with low toxicity and high potency for glioma treatment. The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier. By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics, we can maximize their therapeutic value and minimize adverse effects. Considering the complex nature of glioblastoma, these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.

Keywords: Glioblastoma; Heterocycles; Kinase pathway; Pyrimidine; Quinazoline.

Figure 1. Glioblastoma WHO grades. CDK4/6: Cyclin-dependent kinase-4/6; IDH: Isocitrate dehydrogenase; EGFR: Epidermal growth factor receptor; MDM2: Mouse double minute 2; PTEN: Phosphatase and tensin homolog.

Figure 2. Kinases targeting pathways in glioblastoma. RTKs: Receptor tyrosine kinases; GRB: Growth factor receptor binder; SOS: Son of sevenless; MEK: Mitogen-activated protein kinase; ERK: Extracellular-signal-regulated kinase; PI3K: Phosphatidylinositol 3-kinase; PIP2: Phosphatidylinositol 4, 5-bisphosphate; PIP3: Phosphatidylinositol 3, 4, 5 trisphosphate; PDK: Phosphoinositide-dependent protein kinase; mTOR: mammalian target of rapamycin; MDM2: Mouse double minute 2; JAK: Janus kinase; STAT: Signal transducers and activators of transcription.

Figure 3. Chemical structures of pyrimidine containing heterocycles.

Figure 4. Chemical structures of quinoline, isoquinoline, quinoxaline and quinazoline containing heterocycle.

Figure 5. Chemical structures of thiazole and thiadiazol containing heterocycle.

Figure 6. Chemical structures of imidazole containing heterocycle.

Figure 7. Chemical structures of indole containing heterocycle.

Figure 8. Chemical structures of acridone containing heterocycle.

Figure 9. Chemical structures of triazine containing heterocycle.

Figure 10. Chemical structures of other heterocycle against glioma.

Figure 11. Chemical structures of novel derivatives against glioma.