PO.ET09.01 · 实验与分子治疗
CTS2190，一种处于I/II期临床开发中的首创PRMT1抑制剂，展现出稳健而广泛的单药疗效，并基于转化研究发现为新型联合方案提供了理论依据
CTS2190, a first-in-class PRMT1 inhibitor in phase I/II clinical development, demonstrates robust and broad monotherapy efficacy and provides a rationale for novel combinations based on translational findings
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：蛋白精氨酸甲基转移酶1（PRMT1）是一种主要的表观遗传调控因子，通过包括信号转导、DNA损伤修复和免疫逃逸在内的多种机制参与肿瘤发生。CTS2190被设计为一种首创的口服PRMT1抑制剂，以实现高选择性并最大限度地减少脱靶毒性。该药物目前正在I/II期临床试验（NCT06224387）中接受评估，在经过大量既往治疗的晚期实体瘤患者中显示出令人鼓舞的疗效和良好的安全性特征，未观察到血栓事件。
方法：通过生化和细胞检测表征了CTS2190的效力和选择性。在多个细胞来源异种移植（CDX）和患者来源异种移植（PDX）模型中评估了其单药疗效。此外，在相关的体内模型中，研究了CTS2190与靶向疗法（Enzalutamide、Osimertinib、Gilteritinib）、放射性配体疗法（Lu177-PSMA）和抗PD-1抗体的联合潜力。评估了肿瘤生长和免疫特征分析。
结果：CTS2190对PRMT1表现出高选择性，并作为单药在各种CDX和PDX模型中展现出强效的剂量依赖性抗肿瘤活性，导致显著的肿瘤生长抑制。这种稳健的单药疗效为探索联合方案奠定了坚实基础。CTS2190与所有联合伙伴均展现出稳健的协同抗肿瘤活性。它增强了靶向药物的疗效，使肿瘤对放射敏感，并重塑了肿瘤免疫微环境。
结论：CTS2190在临床前模型中令人信服的单药活性印证了其正在进行的临床研究。与靶向、放射性配体和免疫治疗药物观察到的广泛而强效的协同作用，为即将到来的基于CTS2190的新型联合方案的临床开发提供了强有力的机制依据，使其成为多种癌症的一种通用治疗策略。
查看英文原文 English abstract
Background: Protein arginine methyltransferase 1 (PRMT1) is a master epigenetic regulator implicated in oncogenesis through diverse mechanisms, including signal transduction, DNA damage repair, and immune evasion. CTS2190 was designed as a first-in-class, oral PRMT1 inhibitor to achieve high selectivity and minimize off-target toxicity. This agent is currently being evaluated in a phase I/II clinical trial (NCT06224387) and has shown encouraging efficacy and a favorable safety profile, with no thrombotic events observed, in heavily pretreated patients with advanced solid tumors.
Methods: The potency and selectivity of CTS2190 were characterized through biochemical and cellular assays. Its monotherapy efficacy was evaluated in multiple cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Furthermore, the combinatorial potential of CTS2190 was investigated with targeted therapies (Enzalutamide, Osimertinib, Gilteritinib), a radioligand therapy (Lu177-PSMA), and an anti-PD-1 antibody across relevant in vivo models. Tumor growth and immune profiling were assessed.
Results: CTS2190 exhibited high selectivity for PRMT1 and potent dose-dependent antitumor activity as a single agent in various CDX and PDX models, leading to significant tumor growth inhibition. This robust monotherapy efficacy provided a strong foundation for exploring combinations. CTS2190 demonstrated robust synergistic antitumor activity with all combination partners. It enhanced the efficacy of targeted agents, sensitized tumors to radiation, and remodeled the tumor immune microenvironment.
Conclusion: The compelling single-agent activity of CTS2190 in preclinical models corroborates its ongoing clinical investigation. The broad and potent synergy observed with targeted, radioligand, and immunotherapeutic agents provides a strong mechanistic rationale for the imminent clinical development of novel CTS2190-based combination regimens, positioning it as a versatile therapeutic strategy for multiple cancers.
利益披露 Disclosure
H. Shi,
CytosinLab Therapeutics Co., Ltd. Employment.
Q. Ouyang,
CytosinLab Therapeutics Co., Ltd. Employment.
J. Huang,
CytosinLab Therapeutics Co., Ltd. Employment.
X. Fu,
CytosinLab Therapeutics Co., Ltd. Employment.
G. Xu,
CytosinLab Therapeutics Co., Ltd. Other, co-founder.
H. Wu,
CytosinLab Therapeutics Co., Ltd. Other, founder.