PO.ET09.04 · 实验与分子治疗
RCZY-690：一种三元复合物分子胶泛RAS（ON）抑制剂，在RAS依赖性实体瘤中展现出同类最佳潜力
RCZY-690: A tri-complex molecular glue pan-RAS (ON) inhibitor exhibiting best-in-class potential for RAS-addicted solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
RAS家族（包括HRAS、KRAS和NRAS）作为主要的分子开关，调控包括细胞生长、增殖、存活和分化在内的关键细胞过程，并与癌症密切相关。作为小GTP酶超家族的成员，RAS蛋白在活性（GTP结合）状态和非活性（GDP结合）状态之间循环，以控制MAPK/ERK和PI3K/AKT等关键信号通路。致癌性RAS突变——大多发生在第12、13和61密码子——损害内源性或GAP刺激的GTP水解，使平衡向活性的GTP结合形式偏移。这种持续激活导致下游信号的组成性激活，驱动不受控的细胞增殖、增强的存活和肿瘤发生。RCZY-690是一种高效、口服生物利用度高的三元复合物分子胶泛RAS（ON）抑制剂，具有同类最佳潜力。它特异性靶向处于活性GTP结合（ON）状态的突变型和野生型RAS蛋白，从而阻断RAS与下游效应分子的结合并破坏致癌信号转导。在多种RAS突变细胞系中，与RMC-6236相比，RCZY-690对细胞增殖表现出显著更强的抑制作用，并对下游p-ERK水平产生更深度的抑制。RCZY-690具有良好的ADME和PK特性，可实现更高的暴露量、延长的半衰期（T1/2）以及平缓的Cmax/Ctrough浓度-时间曲线，与改善的治疗指数（TI）相符。与RMC-6236和ERAS-0015相比，它在小鼠模型中显示出更高程度的优先肿瘤分布。这些优势使RCZY-690在KRAS突变的CDX和同源肿瘤小鼠模型中，能够以低至RMC-6236剂量的1/25至1/250以及ERAS-0015剂量的1/3至1/10的剂量实现相当的肿瘤生长抑制（TGI）。RCZY-690展现出良好的PK/PD特征，包括比RMC-6236更持久的DUSP6抑制，以及在临床前毒性研究中优异的体内耐受性和有前景的安全窗。综上所述，这些特性使RCZY-690成为一种有前景的泛RAS（ON）抑制剂，并支持其推进至计划于2026年第二季度提交的新药临床研究（IND）申请。
查看英文原文 English abstract
The RAS family, including HRAS, KRAS, and NRAS, acts as a master molecular switch that regulates essential cellular processes, including cell growth, proliferation, survival, and differentiation, and is strongly implicated in cancer. As members of the small GTPase superfamily, RAS proteins cycle between an active (GTP-bound) state and an inactive (GDP-bound) state to control key signaling pathways such as the MAPK/ERK and PI3K/AKT. Oncogenic RAS mutations- mostly occur at codons 12, 13, and 61-impair intrinsic or GAP-stimulated GTP hydrolysis, and shifting the equilibrium toward the active, GTP-bound form of RAS. This persistent activation leads to constitutive downstream signaling, driving uncontrolled cell proliferation, enhanced survival, and tumorigenesis. RCZY-690 is a highly potent, orally bioavailable tri-complex molecular glue pan-RAS (ON) inhibitor with Best-in-Class potential. It specifically targets both mutant and wild-type RAS proteins in their active GTP-bound (ON) state, thereby blocking RAS engagement with downstream effectors and disrupting oncogenic signal transduction. In multiple RAS-mutant cell lines, RCZY-690 exhibited significantly greater inhibition of cell proliferation and more profound suppression of downstream p-ERK levels compared with RMC-6236. RCZY-690 has favorable ADME and PK properties, achieving higher exposure, an extended half-life (T 1/2 ), and a flat Cmax/Ctrough concentration-time profile consistent with an improved therapeutic index (TI). Compared to RMC-6236 and ERAS-0015, it shows higher degree of preferential tumor distribution in mouse models. These advantages enable RCZY-690 to achieve comparable tumor growth inhibition (TGI) at doses as low as 1/25th to 1/250th those of RMC-6236 and 1/3rd to 1/10th those of ERAS-0015 across KRAS-mutant CDX and syngeneic tumor mouse models. RCZY-690 demonstrates favorable PK/PD profiles, including more durable DUSP6 suppression than RMC-6236, alongside excellent in vivo tolerability and promising safety margins in preclinical toxicity studies. Taken together, these attributes position RCZY-690 as a promising pan-RAS(ON) inhibitor and support its advancement toward an Investigational New Drug (IND) filing planned for Q2 2026.
利益披露 Disclosure
X. Chen, None..
L. Wang, None..
X. Liu, None..
Q. You, None..
S. Li, None..
L. Wang, None..
S. Bi, None..
J. Jiang, None..
J. Bao, None.