GenFleet Therapeutics, a commercial-stage biopharmaceutical company focusing on cutting-edge therapies in oncology and immunology, today announced the latest preclinical findings of GFH276, an IND-enabling oral Pan RAS (ON) inhibitor, at the poster presentation of the 2025 American Association for Cancer Research (AACR) Annual Meeting. .

健帆药业（GenFleet Therapeutics），一家专注于肿瘤学和免疫学前沿疗法的商业阶段生物制药公司，今天在2025年美国癌症研究协会（AACR）年会的海报展示环节上，公布了其IND申报阶段口服泛RAS（ON）抑制剂GFH276的最新临床前研究结果。

GFH276 is developed with the novel mechanism by recruiting intracellular cyclophilin A (CypA) protein to target RAS proteins across most wild-type/mutant subtypes, and exerted potent anti-tumor activities in cellular & tumor models harboring RAS mutations or RTK alterations. In preclinical research, GFH276 also demonstrated profound inhibition of MAPK signaling pathway.

GFH276通过招募细胞内亲环蛋白A（CypA）靶向大多数野生型/突变亚型的RAS蛋白，发挥强大的抗肿瘤活性，在携带RAS突变或RTK改变的细胞和肿瘤模型中表现出显著效果。在临床前研究中，GFH276还显示出对MAPK信号通路的深度抑制作用。

Across multiple KRAS-mutant tumor models, GFH276 displayed superior pharmacokinetic properties and achieved equivalent or enhanced tumor regression at substantially lower effective dosages compared to overseas Pan RAS inhibitor. Notably, GFH276 exhibited high selectivity with no off-target activity in kinase screening or safety evaluation, and cellular assays suggested the potential of GFH276 to overcome multiple drug resistances induced by diverse mechanisms..

在多个KRAS突变肿瘤模型中，GFH276展现了优越的药代动力学特性，并在显著更低的有效剂量下实现了与海外Pan RAS抑制剂相当或更强的肿瘤消退效果。值得注意的是，GFH276在激酶筛选和安全性评估中表现出高选择性，无脱靶活性，且细胞实验表明GFH276有克服多种机制诱导的多重耐药性的潜力。

GFH276: A molecular glue Pan RAS (ON) inhibitor with broad spectrum anti-tumor activitiesAbstract（No.: 389）

GFH276：一种具有广谱抗肿瘤活性的分子胶Pan RAS（ON）抑制剂 摘要（编号：389）

Inhibition of most GTP-bound wild-type/mutant RAS subtypes and the downstream MAPK signaling pathway

抑制大多数GTP结合的野生型/突变型RAS亚型及下游MAPK信号通路

GFH276 is a molecular glue Pan RAS inhibitor that targets most GTP-bound wild-type and mutant RAS subtypes, by reshaping and repurposing intracellular CypA into the CypA-GFH276-RAS tripartite complex. GFH276 was also observed with potent growth inhibition across an array of KRAS-mutant or RTK-altered cell lines.Notably, GFH276 demonstrated rapid and deep inhibition of phospho-ERK1/2 levels in the MAPK pathway across KRAS-mutant cellular & tumor models.

GFH276是一种分子胶泛RAS抑制剂，通过重塑和重新利用细胞内CypA形成CypA-GFH276-RAS三元复合物，靶向大多数GTP结合的野生型和突变型RAS亚型。GFH276在多种KRAS突变或RTK改变的细胞系中显示出强大的生长抑制作用。值得注意的是，GFH276在KRAS突变的细胞和肿瘤模型中表现出对MAPK通路中磷-ERK1/2水平的快速而深度的抑制作用。

By activating downstream signaling pathways like the MAPK cascade, RAS plays a key role in regulating essential cellular processes including proliferation, migration and survival..

通过激活下游信号通路（如MAPK级联），RAS在调控细胞增殖、迁移和存活等关键过程中发挥重要作用。

Equivalent/enhanced tumor regression at much lower effective dosages and superior PK properties compared to overseas Pan RAS inhibitor

与海外Pan RAS抑制剂相比，在更低的有效剂量下达到相当或增强的肿瘤消退，并具有更优的药代动力学特性。

Over 2-3 weeks’ continuous dosing, GFH276 outperformed RMC-6236 across non-small cell lung cancer, pancreatic cancer, and colorectal cancer models harboring KRAS mutations (G12C, G12D, G12V and G13D etc.): GFH276 demonstrated dose-dependent anti-tumor activity at oral dosages of 0.3-3 mg/kg QD; GFH276 also exhibited equivalent or greater tumor regression at oral dosages of 1 or 3 mg/kg QD, compared to the oral administration of RMC-6236 at 10 mg/kg QD.

在连续2-3周的给药过程中，GFH276在携带KRAS突变（G12C、G12D、G12V和G13D等）的非小细胞肺癌、胰腺癌和结直肠癌模型中表现优于RMC-6236：GFH276在0.3-3 mg/kg QD的口服剂量下显示出剂量依赖性的抗肿瘤活性；与每日口服10 mg/kg RMC-6236相比，GFH276在1或3 mg/kg QD的口服剂量下也表现出相同或更强的肿瘤消退效果。

The advantage of GFH276 in much lower effective dosages is associated with its better pharmacokinetic properties: GFH276’s clearance rate in animal models was significantly lower than that of RMC-6236, while the oral bioavailability of GFH276 markedly higher. Moreover, GFH276 showed no off-targets activity in kinase selectivity and safety assessment, indicating its safety profile and target specificity..

GFH276在更低有效剂量下的优势与其更优的药代动力学特性相关：GFH276在动物模型中的清除率显著低于RMC-6236，而GFH276的口服生物利用度明显更高。此外，GFH276在激酶选择性和安全性评估中未显示出脱靶活性，表明其安全性和靶标特异性。

Therapeutic potential to overcome multiple resistances

克服多重耐药性的治疗潜力

RTK proteins can be reactivated by EGF stimulation and induced adaptive resistance. Compared to SIIP-based KRAS G12C inhibitors, GFH276 is not susceptible to upstream RTK reactivation by EGF stimulation; the suppression of p-ERK1/2 phosphorylation was barely affected in cellular assays, showcasing the mechanistic advantage of GFH276 in addressing the adaptive resistance.

RTK蛋白可以通过EGF刺激重新激活并诱导适应性耐药。与基于SIIP的KRAS G12C抑制剂相比，GFH276不易受EGF刺激引起的上游RTK重新激活的影响；在细胞实验中，对p-ERK1/2磷酸化的抑制几乎未受影响，展示了GFH276在解决适应性耐药方面的机制优势。

Additionally, GFH276 remained effective across cell lines carrying various acquired resistances to first-generation marketed KRAS inhibitors, highlighting the therapeutic potential of GFH276 as next-generation Pan RAS inhibitor in overcoming multiple resistances..

此外，GFH276在携带对第一代上市KRAS抑制剂的各种获得性耐药性的细胞系中仍然有效，突显了GFH276作为下一代泛RAS抑制剂在克服多种耐药性方面的治疗潜力。

About RAS and GFH276

关于RAS和GFH276

RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAF-MEK-ERK、PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans.GFH276 is an oral novel small-molecule Pan RAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins.

RAS蛋白以活性GTP结合态或非活性GDP结合态存在，是控制信号通路中细胞反应的二元分子开关，包括RAF-MEK-ERK、PI3K/AKT/mTOR。三个RAS基因编码蛋白质异构体，分别是Kirsten Ras（KRAS）、Harvey Ras（HRAS）和神经母细胞瘤Ras（NRAS），其中KRAS是人类中最常见的突变癌基因。GFH276是一种口服新型小分子Pan RAS（ON）抑制剂，通过劫持Cyp A来靶向大多数野生型/突变亚型的活性GTP结合态RAS蛋白，包括最常见的KRAS突变（G12C、G12D、G12V等）蛋白。

Preclinical research of GFH276 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH276 is also superior to the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance..

GFH276的临床前研究展示了剂量依赖性的抗肿瘤活性，并在多种KRAS突变肿瘤模型中驱动肿瘤消退。GFH276还优于主流的基于SIIP（switch II pocket）的KRAS抑制剂，能够更好地克服适应性和获得性耐药。