Nutshell Therapeutics (Shanghai) Co., Ltd. received US FDA clearance for an investigational new drug application covering NTS231, a covalent allosteric molecular glue degrader of NRF2, clearing the program to enter clinical development in the US.
NTS231 is designed to bind covalently to the Cys151 residue of KEAP1 and promote assembly of the KEAP1-CUL3 E3 ubiquitin ligase complex, triggering proteasomal degradation of NRF2. Constitutive activation of the NRF2 pathway through alterations in NFE2L2, KEAP1, or CUL3 has been associated with treatment resistance across several tumor types, while no approved cancer therapy specifically targets the pathway.
Nutshell said NTS231 was identified using its AI-driven ALLOSTAR allosteric drug discovery platform and progressed from target nomination to IND clearance in 24 months.
In preclinical studies, NTS231 showed dose-dependent antitumor activity across xenograft models carrying NRF2, KEAP1, or CUL3 alterations, including lung squamous cell carcinoma, lung adenocarcinoma, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma. The company also reported enhanced activity when NTS231 was combined with paclitaxel in a chemotherapy-resistant KEAP1-mutant lung squamous cell carcinoma model.