| Autor: |
Maria Ribadeneira, Lili Yao, Paul Ehrlich, Angela Toms, Sylvie Guichard, Sanjeev Forsyth, Blythe Thomson |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Neuro Oncol |
| Popis: |
BACKGROUND Iocitrate dehydrogenase mutations (mIDH1) are present in >70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate (2-HG) causing DNA hypermethylation and promoting tumorigenesis. This abstract summarizes the structure-based design of FT-2102, a potent and selective inhibitor of mutated IDH1-R132 with brain distribution (Kpuu) that is in context of minimal effective concentrations required in brain to modulate 2-HG. METHODS The crystal structure of mutated IDH1 in complex with FT-2102 and NADPH cofactor (2.1A resolution) was determined via sitting-drop vapour-diffusion set-ups. HCT116/IDH1 R132H were implanted in Balb/c nude mice and FT-2102 was administered orally twice daily. FT-2102 and 2-HG levels in plasma and xenografts were determined by LC/MS. In silico and in vitro models were used to determine the extent of brain distribution and ex-vivo rat data was generated to validate the projected distribution into brain tissue (Kpuu). RESULTS In tumor Xenograft (HCT116/IDH1-R132H), FT-2102 inhibits tumor 2-HG production with an IC50 of 24nM which is consistent with its in vitro IC50 of 18nM. FT-2102 unbound plasma concentrations of 256nM in xenografted mice were found to achieve 90% reduction of 2-HG in tumor. Rat data showed that FT-2102 partitions into brain with a Kpuu of 0.45. Based on these data, the concentration of FT-2102 in brain to significantly reduce 2HG is predicted to be 115nM. Recent publications (Natsume, et al, ASCO19) propose 90% reduction of 2-HG (90%) is associated with tumor reduction in the brain. CONCLUSION The structure-based design of FT-2102 has facilitated CNS penetration in animal models and is undergoing evaluation in ongoing clinical trials including patients with CNS based IDH1m tumors (NCT: 03684811). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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