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

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.