CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50–650 mg/m²) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m² days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

CX-5461 是一种 G-四链体稳定剂，在同源重组缺陷模型中表现出合成杀伤力。在这项针对实体瘤患者的多中心 I 期试验中，40 名患者接受了 10 个剂量水平（50-650 mg/m ²）的治疗，以确定推荐的 II 期剂量（主要结果），并评估安全性、耐受性、药代动力学（次要结果）结果）。有缺陷的同源重组被探索为反应的预测生物标志物。CX-5461 通常耐受性良好，推荐的 II 期剂量为 475 mg/m ²每 4 周第 1、8 和 15 天，以及剂量限制性光毒性。在 14% 的患者中观察到反应，主要是在同源重组缺陷的患者中。PALB2 和 BRCA2 的回复突变在种系携带者的初始反应后的进展中被检测到，证实了潜在的合成致死机制。紫外线致敏的体外表征表明，这种毒性与 CX-5461 化学型有关，与 G-四链体合成致死率无关。这些结果为这种 G-quadruplex 稳定剂建立了临床概念验证。Clinicaltrials.gov NCT02719977。