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Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma
Lilian A Patrón1, Helen Yeoman1, Sydney Wilson1
1Reglagene, Inc., Tucson, AZ 85719, USA.
Abstract:
Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, we describe the development of a blood-brain barrier (BBB)-penetrant tubulin destabilizer, RGN3067, for the treatment of GB. RGN3067 shows good oral bioavailability and achieves high concentrations in rodent brains after oral dosing (Cmax of 7807 ng/mL (20 μM), Tmax at 2 h). RGN3067 binds the colchicine binding site of tubulin and inhibits tubulin polymerization. The compound also suppresses the proliferation of the GB cell lines U87 and LN-18, with IC50s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC50 values for RGN3067 range from 148 to 616 nM. Finally, in a patient-derived xenograft (PDX) mouse model, RGN3067 reduces the rate of tumor growth compared to the control. Collectively, we show that RGN3067 is a BBB-penetrant small molecule that shows in vitro and in vivo efficacy and that its design addresses many of the physicochemical properties that prevent the use of microtubule destabilizers as treatments for GB and other brain cancers.
Insights
A novel blood-brain barrier-penetrant tubulin destabilizer, RGN3067, effectively targets glioblastoma. This promising compound demonstrates significant in vitro and in vivo efficacy against brain cancer.
Area of Science:
- Neuro-oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma (GB) is an aggressive brain cancer with poor prognosis.
- Current treatments including surgery, radiation, and temozolomide (TMZ) have limited efficacy due to inevitable tumor recurrence.
- Developing drugs that can effectively cross the blood-brain barrier (BBB) is crucial for treating brain cancers.
Purpose of the Study:
- To develop and characterize a novel blood-brain barrier-penetrant tubulin destabilizer, RGN3067, for glioblastoma treatment.
- To evaluate the physicochemical properties, in vitro efficacy, and in vivo anti-tumor activity of RGN3067.
Main Methods:
- RGN3067 was designed as a BBB-penetrant small molecule targeting tubulin.
- Oral bioavailability and brain penetration were assessed in rodents.
- In vitro cytotoxicity was determined in human glioblastoma cell lines (U87, LN-18, and patient-derived lines).
- In vivo efficacy was evaluated using a patient-derived glioblastoma xenograft mouse model.
Main Results:
- RGN3067 demonstrated good oral bioavailability and achieved high concentrations in rodent brains.
- The compound binds to the colchicine binding site of tubulin, inhibiting polymerization.
- RGN3067 suppressed glioblastoma cell proliferation in vitro with nanomolar IC50 values.
- In vivo studies showed RGN3067 reduced tumor growth rate in a glioblastoma xenograft model.
Conclusions:
- RGN3067 is a BBB-penetrant small molecule with demonstrated in vitro and in vivo efficacy against glioblastoma.
- Its design overcomes limitations of previous microtubule destabilizers for brain cancer treatment.
- RGN3067 represents a potential new therapeutic strategy for glioblastoma and other brain cancers.
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