SHANGHAI

上海

,

，

Sept. 25, 2026

2026年9月25日

/PRNewswire/ -- Nutshell Therapeutics (Shanghai) Co., Ltd. ('Nutshell Therapeutics'), an innovative biotech company focused on AI-driven allosteric drug discovery, announced FDA IND clearance for NTS231, a covalent allosteric molecular glue degrader of NRF2, to launch clinical development in the United States..

/美通社/ -- 专注于人工智能驱动变构药物发现的创新生物科技公司纽壳药业（上海）有限公司（“纽壳药业”）宣布，其NRF2共价变构分子胶降解剂NTS231已获得美国食品药品监督管理局（FDA）的临床试验新药申请（IND）许可，将在美国启动临床开发。

NTS231 is the first NRF2 degrader molecule from China and second globally to enter clinical development.

NTS231 是中国首个、全球第二个进入临床开发的 NRF2 降解剂分子。

This program represents a significant advancement in efforts to therapeutically target the NRF2 pathway, a key driver of tumor survival and treatment resistance in multiple cancer types.

该计划代表了在靶向NRF2通路的治疗努力中取得了重大进展，而NRF2通路是多种癌症类型中肿瘤存活和治疗耐药性的关键驱动因素。

AI-Driven Discovery of a Novel NRF2-Targeting Molecular Glue

人工智能驱动发现新型靶向NRF2的分子胶

The discovery of NTS231 was powered by Nutshell Therapeutics' proprietary AI-driven allosteric drug discovery platform, ALLOSTAR™, which integrates computer-aided drug design (CADD), medicinal chemistry and cutting-edge experimental techniques.

NTS231的发现得益于Nutshell Therapeutics专有的AI驱动变构药物发现平台ALLOSTAR™，该平台整合了计算机辅助药物设计（CADD）、药物化学以及前沿的实验技术。

By leveraging the ALLOSTAR™ platform, Nutshell Therapeutics successfully identified NTS231 as a highly potent and selective novel small molecule that covalently binds to KEAP1 and induces the degradation of NRF2. Mechanistically, NTS231 irreversibly links to the Cys151 residue of KEAP1 and stabilizes the KEAP1 structural conformation conducive to CUL3 interaction as well as the assembly of functional KEAP1–CUL3 E3-ligase complex, thereby driving NRF2 degradation, suppressing NRF2 signaling pathway, and inhibiting cancer cell viability.

借助ALLOSTAR™平台，Nutshell Therapeutics成功鉴定出NTS231，这是一种高效且高选择性的新型小分子，能够与KEAP1共价结合并诱导NRF2降解。在机制上，NTS231不可逆地结合于KEAP1的Cys151残基，稳定有利于CUL3相互作用的KEAP1结构构象，并促进功能性KEAP1–CUL3 E3泛素连接酶复合物的组装，从而驱动NRF2降解，抑制NRF2信号通路，并抑制癌细胞活力。

The team accomplished IND approval within 24 months from target nomination, highlighting AI-enabled acceleration of drug discovery..

该团队在确定靶点后的24个月内获得了新药临床试验（IND）批准，凸显了人工智能加速药物研发的成效。

Robust Preclinical Antitumor Activity and Desirable Safety Profile

稳健的临床前抗肿瘤活性和良好的安全性特征

In preclinical studies, NTS231 exhibits non-inferior in vitro activities to VVD-130037

在临床前研究中，NTS231 表现出与 VVD-130037 非劣效的体外活性

[1]

[1]

, a clinical-stage compound under the same targeting mechanism, while possessing superior pharmacokinetic properties. Across multiple cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring diverse NRF2/KEAP1/CUL3 mutations or NRF2 hyperactivation, NTS231 has demonstrated dose-dependent antitumor efficacy as a single agent in a range of solid tumors, including lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), esophageal squamous cell carcinoma (ESCC), and head and neck squamous cell carcinoma (HNSCC)..

NTS231是一种处于临床阶段的化合物，具有相同的靶向机制，同时拥有更优的药代动力学特性。在携带多种NRF2/KEAP1/CUL3突变或NRF2过度激活的多个细胞来源异种移植（CDX）和患者来源异种移植（PDX）模型中，NTS231作为单药在包括肺鳞状细胞癌（LUSC）、肺腺癌（LUAD）、食管鳞状细胞癌（ESCC）和头颈部鳞状细胞癌（HNSCC）在内的多种实体瘤中均显示出剂量依赖性的抗肿瘤疗效。

NTS231 has also demonstrated the potential for combination therapies. Synergistic antitumor effects were observed when combining NTS231 with chemotherapy, targeted therapies, and antibody-drug conjugates (ADCs). Notably, in chemotherapy-resistant LUSC PDX models harboring KEAP1 and other mutations, the combination of NTS231 and paclitaxel significantly enhanced tumor growth inhibition relative to single agents; in a proof-of-concept CDX model of.

NTS231 还展现了联合治疗的潜力。当 NTS231 与化疗、靶向治疗以及抗体药物偶联物（ADCs）联用时，观察到了协同抗肿瘤效应。值得注意的是，在携带 KEAP1 及其他突变的耐化疗肺鳞状细胞癌（LUSC）患者来源异种移植（PDX）模型中，与单药治疗相比，NTS231 与紫杉醇的联合显著增强了肿瘤生长抑制效果；在一个概念验证性的细胞来源异种移植（CDX）模型中。

NFE2L2

NFE2L2

-amplified LUAD, combined treatment with NTS231 and a TROP2 ADC dramatically improved efficacy and led to tumor regression, accompanied by decreased expression of NRF2-regulated efflux transporters, which might sensitize tumors to ADC payloads and mitigate resistance.

在NRF2扩增的肺腺癌（LUAD）中，NTS231与TROP2抗体偶联药物（ADC）的联合治疗显著提高了疗效并导致肿瘤消退，同时伴有NRF2调控的外排转运蛋白表达下降，这可能使肿瘤对ADC载荷更敏感并减轻耐药性。

In the 28-day Good Laboratory Practice (GLP) toxicology studies conducted in rats and dogs, NTS231 demonstrated a favorable safety profile and a wide safety margin. These findings provide important preclinical support for the continued clinical development of NTS231.

在大鼠和犬中进行的28天良好实验室规范（GLP）毒理学研究中，NTS231展现出良好的安全性特征和较宽的安全窗。这些发现为NTS231的持续临床开发提供了重要的临床前支持。

Targeting a Significant Unmet Need in NRF2-Driven Cancers

针对NRF2驱动癌症中尚未满足的重大需求

Constitutive activation of NRF2 has been observed in many human cancers as a result of genetic alterations in the NRF2-encoding gene

由于编码NRF2的基因发生遗传改变，在许多人类癌症中观察到NRF2的组成性激活。

NFE2L2

NFE2L2

and its regulatory genes

及其调控基因

KEAP1

KEAP1

and

和

CUL3

CUL3

. Approximately 12% of cancer patients profiled in The Cancer Genome Atlas (TCGA) database carry mutations in at least one of the three genes

在癌症基因组图谱（TCGA）数据库中，约有12%的癌症患者携带至少三个基因中的一个基因的突变。

NFE2L2

NFE2L2

,

，

KEAP1

KEAP1

or

或

CUL3

CUL3

, particularly prevalent in >30% LUSC and >20% LUAD.  Preliminary estimates indicate over

，在超过30%的肺鳞状细胞癌（LUSC）和超过20%的肺腺癌（LUAD）中尤为普遍。初步估计表明超过

1.5 million annual new cancer cases worldwide

全球每年新增癌症病例150万例

harbor NRF2/KEAP1/CUL3 alterations or other aberrant NRF2 pathway activation.

存在NRF2/KEAP1/CUL3改变或其他NRF2通路异常激活。

[2]

[2]

This patient population is largely ineligible for most targeted therapies, given that NRF2/KEAP1/CUL3 alterations are mutually exclusive with EGFR, ALK, ROS1, and BRAF genetic lesions. Immunotherapy likewise yields limited efficacy, since such mutations are strongly associated with an immunologically cold tumor microenvironment (TME) that leads to therapeutic resistance.

鉴于NRF2/KEAP1/CUL3改变与EGFR、ALK、ROS1和BRAF基因病变互斥，该患者群体大多不符合大多数靶向治疗的适用条件。免疫疗法同样疗效有限，因为此类突变与免疫冷肿瘤微环境（TME）密切相关，从而导致治疗耐药。

Constant activation of the NRF2 pathway resulting from mutations in NRF2, KEAP1 or CUL3 can also confer resistance to standard chemotherapy. Collectively, these factors underscore the substantial unmet medical need for effective therapies targeting NRF2-driven tumor biology..

NRF2、KEAP1 或 CUL3 突变导致的 NRF2 通路持续激活，也可能赋予肿瘤对标准化疗的耐药性。综上所述，这些因素凸显了针对 NRF2 驱动的肿瘤生物学开发有效疗法的巨大未满足医疗需求。

By directly targeting the KEAP1–NRF2 regulatory axis, NTS231 has the potential to provide a new therapeutic approach for patients with NRF2, KEAP1, or CUL3 mutations, as well as tumors characterized by NRF2 pathway hyperactivation.

通过直接靶向KEAP1–NRF2调控轴，NTS231有望为携带NRF2、KEAP1或CUL3突变的患者，以及以NRF2通路过度激活为特征的肿瘤提供一种新的治疗策略。

[1]

[1]

Li, Q. et al. NTS231 is a novel covalent allosteric molecular glue of the KEAP1-CUL3 E3-ligase complex that selectively degrades NRF2 and inhibits tumors with aberrant NRF2 activation [abstract]. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 22–26, 2025; Boston, MA. .

李，Q. 等人。NTS231 是一种新型的 KEAP1-CUL3 E3 连接酶复合物的共价别构分子胶，可选择性降解 NRF2 并抑制具有异常 NRF2 激活的肿瘤 [摘要]。发表于 AACR-NCI-EORTC 国际分子靶点与癌症治疗会议；2025 年 10 月 22–26 日；马萨诸塞州波士顿。

Mol Cancer Ther

分子癌症治疗学

2025;24(10 Suppl):Abstract B108.

2025;24(10 增刊):摘要 B108.

[2]

[2]

Cerami, E. et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data.

Cerami, E. 等。cBio 癌症基因组学门户：一个用于探索多维癌症基因组学数据的开放平台。

Cancer Discovery

癌症发现

2012;2, 401–404.

2012；2：401–404。

About Nutshell Therapeutics

关于 Nutshell Therapeutics

Nutshell Therapeutics (Shanghai) Co., Ltd.

坚果壳治疗学（上海）有限公司

is an innovative biotechnology company leveraging artificial intelligence and allosteric drug discovery to develop small-molecule therapeutics against historically challenging and 'undruggable' targets. Founded by Professor Zhang Jian, a recognized pioneer in the field of allosteric drug discovery, Nutshell Therapeutics has built an integrated R&D team with expertise spanning artificial intelligence, medicinal chemistry, pharmacology, toxicology, and clinical development.

是一家创新型生物技术公司，利用人工智能和变构药物发现技术，开发针对历史上具有挑战性且“不可成药”靶点的小分子疗法。Nutshell Therapeutics 由变构药物发现领域的公认先驱张建教授创立，已组建一支集成研发团队，其专业知识涵盖人工智能、药物化学、药理学、毒理学和临床开发。

The company has focused on small-molecule drug discovery based on protein conformational regulation and has developed an integrated discovery platform combining computational and experimental approaches. Nutshell Therapeutics operates a 1,500-square-meter R&D center in Shanghai integrating computational and experimental research capabilities.

该公司专注于基于蛋白质构象调控的小分子药物发现，并开发了一个结合计算与实验方法的集成发现平台。Nutshell Therapeutics 在上海运营着一家1,500平方米的研发中心，整合了计算与实验研究能力。

The company has raised tens of millions of U.S. dollars from multiple established venture capital investors..

该公司已从多家知名风险投资机构筹集了数千万美元。

SOURCE Nutshell Therapeutics (Shanghai) Co., Ltd.

来源：纽石泰克（上海）有限公司

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