China-based Nutshell Therapeutics has received Investigational New Drug (IND) clearance in the US for NTS231, a highly active and selective allosteric molecular glue that covalently binds the Cys151 residue of KEAP1, stabilises the KEAP1–CUL3 E3 ligase complex, and drives degradation of NRF2 to block the survival pathway in NRF2-dependent tumours.

NTS231 is the first China-developed and the second globally to enter the clinic for this target mechanism. It is built on the company's AI-driven ALLOSTAR platform, which combines computer-aided drug design with medicinal chemistry to achieve high-specificity covalent engagement of KEAP1.

The asset addresses a clear unmet need in solid tumours: loss-of-function mutations in KEAP1 and CUL3, or gain-of-function mutations in NRF2, are prevalent in lung squamous cell carcinoma (SCC) at over 30% and lung adenocarcinoma at over 20%, and NTS231 showed dose-dependent antitumour activity across CDX and PDX models of lung squamous, oesophageal squamous, and head-and-neck squamous carcinoma with NRF2 pathway activation.

Beyond monotherapy, NTS231 demonstrated synergy with paclitaxel in chemotherapy-resistant, KEAP1-mutant lung squamous PDX models, and 28-day GLP toxicology studies in rats and dogs showed a wide safety margin, supporting combination development with chemotherapy, targeted agents, and ADCs.

The IND clearance lands days after the company's Series C1 raise.