PO.ET09.09 · 实验与分子治疗
CS231295——一种新型AURKB偏向性多激酶抑制剂，在RB1缺陷型肿瘤中展现出合成致死效应及强效的颅内疗效
CS231295, a novel AURKB-biased multi-kinase inhibitor, demonstrates synthetic lethality in RB1-deficient tumors and potent intracranial efficacy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：靶向Aurora激酶B（AURKB）的多激酶抑制剂的临床开发常因同时抑制VEGFR所致的剂量限制性毒性而受限，无法实现对AURKB靶点的最佳抑制。CS231295被设计为一种AURKB偏向性抑制剂，以克服这一挑战。
方法：采用生化和细胞学检测进行激酶谱分析。RB1生物标志物验证采用等基因NCI-H1048-tet-on-RB1模型。在RB1缺陷型SCLC细胞来源及患者来源异种移植模型中评估体内疗效和药代动力学。在原位脑肿瘤模型中评价脑穿透性和颅内疗效。
结果：CS231295强效抑制AURKB（IC50 = 1.32 nM），并具有均衡的多激酶谱。关键在于，其直接抗肿瘤活性——以0.3–3 μM浓度下caspase-3/9的切割为证据——发生的浓度与产生抗血管生成效应所需浓度（HUVEC成管抑制为3–6 μM）重叠或更低，提示存在潜在的协同治疗窗口。CS231295还展现出与RB1缺陷的合成致死关系，与RB1野生型相比，在RB1缺陷型小细胞肺癌（SCLC）细胞中表现出更高的细胞毒性。RB1在NCI-H1048细胞中过表达使IC50从0.671 μM升至8.389 μM，证实RB1缺陷是关键的敏感性标志物。口服给药在RB1缺陷型SCLC模型中诱导了显著的肿瘤消退。显著的脑穿透性（脑–血浆比≈1）与颅内肿瘤模型中的强效疗效相关。
结论：CS231295在同时调节血管生成的剂量下即可实现有效的AURKB抑制，克服了既往药物的一个关键局限。其与RB1缺陷的合成致死效应及显著的颅内疗效支持其对RB1缺陷型恶性肿瘤及累及脑部的肿瘤的治疗潜力。已在中国和美国获得IND批准，为全球临床开发提供了便利。
查看英文原文 English abstract
Background: The clinical development of multi-kinase inhibitors targeting Aurora kinase B (AURKB) is often limited by dose-limiting toxicities from concurrent VEGFR inhibition, preventing optimal AURKB target suppression. CS231295 was designed as an AURKB-biased inhibitor to overcome this challenge.
Methods: Kinase profiling was performed using biochemical and cellular assays. RB1 biomarker validation employed an isogenic NCI-H1048-tet-on-RB1 model. In vivo efficacy and pharmacokinetics were assessed in RB1-deficient SCLC cell-derived and patient-derived xenograft models. Brain penetration and intracranial efficacy were evaluated in orthotopic brain tumor models.
Results: CS231295 potently inhibits AURKB (IC₅₀ = 1.32 nM) with a balanced multi-kinase profile. Crucially, its direct antitumor activity-evidenced by caspase-3/9 cleavage at 0.3-3 μM-occurs at concentrations overlapping with or below those needed for anti-angiogenic effects (HUVEC tube inhibition at 3-6 μM), indicating a potential synergistic therapeutic window. CS231295 also demonstrated a synthetic lethal relationship with RB1 deficiency, exhibiting heightened cytotoxicity in RB1-deficient compared to RB1-wildtype small cell lung cancer (SCLC) cells. RB1 overexpression in NCI-H1048 cells increased the IC₅₀ from 0.671 μM to 8.389 μM, confirming RB1 deficiency as a key sensitivity marker. Oral administration induced significant tumor regression in RB1-deficient SCLC models. Prominent brain penetration (brain-to-plasma ratio ≈1) correlated with robust efficacy in an intracranial tumor model.
Conclusion: CS231295 achieves effective AURKB inhibition at doses concurrently modulating angiogenesis, overcoming a key limitation of prior agents. Its synthetic lethality with RB1 deficiency and marked intracranial efficacy support its therapeutic potential for RB1-deficient malignancies and brain-involved tumors. IND approvals have been obtained in China and the U.S., facilitating global clinical development.
利益披露 Disclosure
Y. Zhou, None..
Q. Yang, None..
Q. Xia, None..
Y. Zhang, None..
Z. Li, None..
D. Pan, None..
S. Shan, None.