Patrón Lilian A, Yeoman Helen, Ramos Joseph, Risinger April L, Gokhale Vijay, Suzuki Teri C
Reglagene, Inc., Houston, Texas.
Department of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Mol Cancer Ther. 2025 Aug 1;24(8):1129-1144. doi: 10.1158/1535-7163.MCT-24-1208.
Glioblastoma (GBM) 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 (MTA) 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 cancers. The development of novel MTAs with good BBB penetrance, decreased toxicity, and an ability to overcome drug-induced resistance is an attractive prospect. In this study, 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 GBM 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 = 3,530 ng/g) and rats (Cmax = 1,667 ng/g). Drug efficacy was confirmed in two xenograft models. In a temozolomide-resistant LN-18 GBM 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 GBM 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 GBM.
胶质母细胞瘤（GBM）是成人中最常见且侵袭性最强的恶性脑肿瘤，中位生存期约为15个月。鉴于目前获批治疗方法的生存率较低，迫切需要新的疗法。微管靶向药物（MTA）是最成功的癌症一线治疗方法之一；然而，已获批的MTA无法穿过血脑屏障（BBB）限制了它们在中枢神经系统癌症中的应用。开发具有良好BBB渗透性、降低毒性且能够克服药物诱导抗性的新型MTA是一个有吸引力的前景。在本研究中，我们描述了RGN6024的特性，它是一种可穿透脑的小分子微管蛋白去稳定剂，能结合微管蛋白的秋水仙碱结合位点。在活力测定中，RGN6024对GBM细胞系具有优异的体外效力，IC50值在低至中纳摩尔范围内。RGN6024对常见的耐药机制不太敏感；其活性不受βIII-微管蛋白过表达的影响，并且在体内小鼠和大鼠模型中显示出良好的血脑渗透性。通过口服给药，RGN6024在小鼠（Cmax = 3530 ng/g）和大鼠（Cmax = 1667 ng/g）中均显示出优异的BBB渗透性。在两种异种移植模型中证实了药物疗效。在对替莫唑胺耐药的LN-18 GBM异种移植模型中，当以7.5或15 mg/kg口服给药时，RGN6024显示出肿瘤生长减缓。此外，RGN6024在原位小鼠模型中抑制了BT142 GBM细胞的生长并显著延长了生存期。综上所述，这些数据为开发RGN6024用于治疗GBM提供了支持。
