Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/12/2/406 |
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| author | Lilian A. Patrón Helen Yeoman Sydney Wilson Nanyun Tang Michael E. Berens Vijay Gokhale Teri C. Suzuki |
| author_facet | Lilian A. Patrón Helen Yeoman Sydney Wilson Nanyun Tang Michael E. Berens Vijay Gokhale Teri C. Suzuki |
| author_sort | Lilian A. Patrón |
| collection | DOAJ |
| description | 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 (C<sub>max</sub> of 7807 ng/mL (20 μM), T<sub>max</sub> 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 IC<sub>50</sub>s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC<sub>50</sub> 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. |
| first_indexed | 2024-03-07T22:40:22Z |
| format | Article |
| id | doaj.art-1c13069713c0462e862226d57ef4f263 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-07T22:40:22Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-1c13069713c0462e862226d57ef4f2632024-02-23T15:08:44ZengMDPI AGBiomedicines2227-90592024-02-0112240610.3390/biomedicines12020406Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of GlioblastomaLilian A. Patrón0Helen Yeoman1Sydney Wilson2Nanyun Tang3Michael E. Berens4Vijay Gokhale5Teri C. Suzuki6Reglagene, Inc., Tucson, AZ 85719, USAReglagene, Inc., Tucson, AZ 85719, USAReglagene, Inc., Tucson, AZ 85719, USATranslational Genomics Research Institute (TGen), Phoenix, AZ 85004, USATranslational Genomics Research Institute (TGen), Phoenix, AZ 85004, USAReglagene, Inc., Tucson, AZ 85719, USAReglagene, Inc., Tucson, AZ 85719, USAGlioblastoma (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 (C<sub>max</sub> of 7807 ng/mL (20 μM), T<sub>max</sub> 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 IC<sub>50</sub>s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC<sub>50</sub> 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.https://www.mdpi.com/2227-9059/12/2/406glioblastomabrain cancerssmall moleculesmicrotubulestubulin destabilizer |
| spellingShingle | Lilian A. Patrón Helen Yeoman Sydney Wilson Nanyun Tang Michael E. Berens Vijay Gokhale Teri C. Suzuki Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma Biomedicines glioblastoma brain cancers small molecules microtubules tubulin destabilizer |
| title | Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma |
| title_full | Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma |
| title_fullStr | Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma |
| title_full_unstemmed | Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma |
| title_short | Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma |
| title_sort | novel brain penetrant small molecule tubulin destabilizers for the treatment of glioblastoma |
| topic | glioblastoma brain cancers small molecules microtubules tubulin destabilizer |
| url | https://www.mdpi.com/2227-9059/12/2/406 |
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