Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations
| Autor: | Assia Shisheva, Ognian C. Ikonomov, Diego Sbrissa |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Drug Programmed cell death media_common.quotation_subject Aminopyridines Antineoplastic Agents Toxicology Translational Research Biomedical Phosphatidylinositol 3-Kinases 03 medical and health sciences PIKFYVE 0302 clinical medicine Neoplasms medicine Animals Humans media_common Pharmacology Chemistry Cancer medicine.disease Small molecule 030104 developmental biology 030220 oncology & carcinogenesis Toxicity Cancer cell Cancer research Heterocyclic Compounds 3-Ring Cytoplasmic Vacuolation Protein Binding |
| Zdroj: | Toxicology and Applied Pharmacology. 383:114771 |
| ISSN: | 0041-008X |
| Popis: | Through synthesis of two rare phosphoinositides, PtdIns(3,5)P2 and PtdIns5P, the ubiquitously expressed phosphoinositide kinase PIKfyve is implicated in pleiotropic cellular functions. Small molecules specifically inhibiting PIKfyve activity cause cytoplasmic vacuolation in all dividing cells in culture yet trigger non-apoptotic death through excessive vacuolation only in cancer cells. Intriguingly, cancer cell toxicity appears to be inhibitor-specific suggesting that additional targets beyond PIKfyve are affected. One PIKfyve inhibitor – apilimod - is already in clinical trials for treatment of B-cell malignancies. However, apilimod is inactivated in cultured cells and exhibits unexpectedly low plasma levels in patients treated with maximum oral dosage. Thus, the potential widespread use of PIKfyve inhibitors as cancer therapeutics requires progress on multiple fronts: (i) advances in methods for isolating relevant cancer cells from individual patients; (ii) delineation of the molecular mechanisms potentiating the vacuolation induced by PIKfyve inhibitors in sensitive cancer cells; (iii) design of PIKfyve inhibitors with favorable pharmacokinetics; and (iv) development of effective drug combinations. |
| Databáze: | OpenAIRE |
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