Shanghai – September 25, 2026 -- Nutshell Therapeutics (Shanghai) Co., Ltd. has received FDA clearance of its Investigational New Drug (IND) application for NTS231, a covalent allosteric molecular glue degrader targeting NRF2, allowing the company to begin clinical development in the United States. NTS231 is the first NRF2 degrader originating from China and only the second such molecule worldwide to reach clinical-stage development.
Nutshell's ALLOSTAR platform compressed discovery-to-IND timeline to 24 months
The company's proprietary AI-driven allosteric drug discovery platform, ALLOSTARTM, which combines computer-aided drug design, medicinal chemistry and experimental screening, identified NTS231 as a potent, selective small molecule. It covalently binds the Cys151 residue of KEAP1, stabilizing a conformation that promotes assembly of the KEAP1–CUL3 E3-ligase complex and drives degradation of NRF2, suppressing downstream signaling and tumor cell viability. Nutshell reached IND clearance 24 months after target nomination.
Preclinical data show non-inferior potency to a rival clinical-stage compound with better pharmacokinetics
In vitro, NTS231 matched the activity of VVD-130037, a clinical-stage compound with the same mechanism, while showing superior pharmacokinetic properties, according to Nutshell. Across cell-derived and patient-derived xenograft models carrying NRF2/KEAP1/CUL3 mutations or NRF2 hyperactivation, NTS231 produced dose-dependent single-agent antitumor activity in lung squamous cell carcinoma, lung adenocarcinoma, esophageal squamous cell carcinoma and head and neck squamous cell carcinoma models.
Combination studies point to synergy with chemotherapy and antibody-drug conjugates
In chemotherapy-resistant lung squamous cell carcinoma PDX models carrying KEAP1 mutations, pairing NTS231 with paclitaxel significantly enhanced tumor growth inhibition versus either agent alone. In an NFE2L2-amplified lung adenocarcinoma CDX model, combining NTS231 with a TROP2-targeted antibody-drug conjugate drove tumor regression and reduced expression of NRF2-regulated efflux transporters, a mechanism that may lower resistance to ADC payloads. Twenty-eight-day GLP toxicology studies in rats and dogs showed a favorable safety profile with a wide safety margin.
NRF2 pathway alterations affect an estimated 1.5 million new cancer cases annually
Roughly 12% of cancer patients profiled in The Cancer Genome Atlas carry mutations in NFE2L2, KEAP1 or CUL3, with prevalence exceeding 30% in lung squamous cell carcinoma and 20% in lung adenocarcinoma. These alterations are mutually exclusive with EGFR, ALK, ROS1 and BRAF mutations, excluding patients from most targeted therapies, while their association with an immunologically cold tumor microenvironment limits immunotherapy efficacy and confers chemotherapy resistance. Nutshell positions NTS231 to address this underserved patient segment by directly disrupting the KEAP1–NRF2 regulatory axis.