Second NRF2 Degrader Enters Clinical Development: Nutshell Therapeutics' NTS231 Received FDA IND Clearance

SHANGHAI, Sept. 25, 2026 /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.

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

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

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.

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

Robust Preclinical Antitumor Activity and Desirable Safety Profile

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

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.

Targeting a Significant Unmet Need in NRF2-Driven Cancers

Constitutive activation of NRF2 has been observed in many human cancers as a result of genetic alterations in the NRF2-encoding gene NFE2L2 and its regulatory genes KEAP1 and CUL3. Approximately 12% of cancer patients profiled in The Cancer Genome Atlas (TCGA) database carry mutations in at least one of the three genes NFE2L2, KEAP1 or CUL3, particularly prevalent in >30% LUSC and >20% LUAD.  Preliminary estimates indicate over 1.5 million annual new cancer cases worldwide harbor NRF2/KEAP1/CUL3 alterations or other aberrant NRF2 pathway activation.^[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. 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.

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.

About Nutshell Therapeutics

Nutshell Therapeutics (Shanghai) Co., Ltd. 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. 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. The company has raised tens of millions of U.S. dollars from multiple established venture capital investors.

SOURCE Nutshell Therapeutics (Shanghai) Co., Ltd.