RGN6024 is a brain-penetrant, small molecule tubulin destabilizer for the treatment of glioblastoma.

in Molecular cancer therapeutics by Lilian A Patrón, Helen Yeoman, Joseph Ramos, April L Risinger, Vijay Gokhale, Teri C Suzuki

TLDR

  • A novel microtubule-targeting agent, RGN6024, shows promise for the treatment of glioblastoma, with high potency against GB cell lines, good blood-brain barrier penetration, and anti-tumor activity in xenograft models.
  • Future studies will be needed to further evaluate RGN6024 as a treatment option for GB, including its potential combination with other therapies and expansion to additional GB cell lines and patient-derived xenograft models.

Abstract

Glioblastoma (GB) is the most common and aggressive malignant brain tumor in adults, with a median survival of ~15 months. Given the poor survival with the currently approved treatments, new therapies are urgently needed. Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies for cancers, however, the inability of approved MTAs to cross the blood-brain barrier (BBB) limits their use for central nervous system (CNS) cancers. The development of novel MTAs with good BBB penetrance, decreased toxicity, and an ability to overcome drug-induced resistance is an attractive prospect. Herein, we describe the characterization of RGN6024, a brain-penetrant small molecule tubulin destabilizer that binds the colchicine binding site of tubulin. RGN6024 has excellent in vitro potency against GB cell lines in viability assays with IC50 values in the low to mid nanomolar range. RGN6024 is less susceptible to common drug resistance mechanisms: its activity is unaffected by βIII-tubulin overexpression and it demonstrates good blood brain penetration in in vivo mouse and rat models. With oral dosing, RGN6024 shows excellent BBB penetration in both mice (Cmax = 3530 ng/g) and rats (Cmax = 1667 ng/g). Drug efficacy was confirmed in two xenograft models. In a TMZ-resistant LN-18 glioblastoma xenograft model, RGN6024 showed a reduction in tumor growth when dosed orally at 7.5 or 15 mg/kg. Additionally, RGN6024 suppressed the growth of BT142 glioblastoma cells in an orthotopic murine model and significantly prolonged survival. Taken together, these data provide support for the development of RGN6024 for the treatment of GB.

Overview

  • The study focuses on developing a novel microtubule-targeting agent, RGN6024, for the treatment of glioblastoma (GB), a common and aggressive malignant brain tumor in adults.
  • RGN6024 is designed to have good blood-brain barrier (BBB) penetrance, decreased toxicity, and the ability to overcome drug-induced resistance, making it an attractive prospect for CNS cancers.
  • The study aims to evaluate the in vitro and in vivo efficacy of RGN6024 and its potential as a treatment option for GB, building upon the success of microtubule-targeting agents in other cancers.

Comparative Analysis & Findings

  • RGN6024 showed excellent in vitro potency against GB cell lines, with IC50 values in the low to mid nanomolar range, making it a promising candidate for further evaluation.
  • RGN6024 demonstrated good blood-brain barrier penetration in in vivo mouse and rat models, with oral dosing resulting in high levels of drug accumulation in the brain.
  • In xenograft models, RGN6024 showed anti-tumor activity, including a reduction in tumor growth in a TMZ-resistant glioblastoma xenograft model and prolonged survival in an orthotopic murine model.

Implications and Future Directions

  • The study provides support for the development of RGN6024 as a potential treatment option for GB, addressing a significant unmet need in the treatment of this aggressive and deadly disease.
  • Future studies could focus on expanding the evaluation of RGN6024 to include additional GB cell lines and patient-derived xenograft models, as well as investigating its potential combination with other therapies.
  • The development of RGN6024 highlights the potential of novel microtubule-targeting agents for the treatment of CNS cancers, and may lead to the discovery of new therapeutic strategies for these diseases.
Read Full Article