US FDA Clears IND for Nutshell Therapeutics' NTS071, a p53 Y220C Reactivator

On April 23, 2025, Nutshell Therapeutics (Shanghai) Co., LTD. received clearance from the U.S. Food and Drug Administration (FDA) to proceed with a Phase 1 clinical trial in the United States for their promising drug candidate, NTS071. This experimental treatment is designed to target the p53 Y220C mutation, a common genetic alteration associated with various types of solid tumors.

NTS071 is an orally administered small molecule that acts as an allosteric reactivator with a unique structural design. It specifically binds to the p53 Y220C mutant protein, enhancing its stability and restoring its ability to bind to DNA effectively. This process reinstates the protein's role in tumor suppression and transcriptional activity, potentially offering a new therapeutic option for certain cancer patients.

The discovery of NTS071 was made possible through Nutshell's proprietary AI-driven drug discovery platform, ALLOSTAR™. This platform focuses on allosteric small molecules, and NTS071 has shown promising preclinical results that suggest it could be the best in its class. The compound exhibits a picomolar-level biochemical activity, making it 20 times more potent than its competitor, PC14586. Moreover, NTS071 outperforms PC14586 in preclinical stability studies, demonstrating better liver microsome and hepatocyte stability across various species, as well as lower in vivo clearance rates and higher oral bioavailability.

Additionally, NTS071 has a lower plasma protein binding rate and a higher free fraction than PC14586, factors that contribute to its potential efficacy in vivo. Importantly, NTS071 does not inhibit the enzyme CYP3A4, a common issue with PC14586 that raises the risk of drug-drug interactions. The compound also boasts a favorable safety profile in non-clinical toxicology studies, indicating a large safety margin.

In preclinical trials, NTS071 displayed dose-dependent anti-tumor activity in multiple patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models with the p53 Y220C mutation. Its efficacy spans a variety of cancer types, including ovarian, lung, gastric, breast, head and neck, esophageal, pancreatic, and bladder cancers. NTS071's performance in these models suggests it could serve as a tumor-agnostic therapy for patients with the p53 Y220C mutation. Compared to PC14586, NTS071 requires significantly lower doses or achieves better efficacy at the same dose, indicating that it might overcome the higher dose limitations of its competitor and offer improved therapeutic outcomes.

Nutshell Therapeutics plans to launch the Phase 1 clinical trial for NTS071 in the second half of 2025, aiming to provide benefits for patients with solid tumors featuring this mutation. The p53 Y220C mutation is prevalent in a broad array of solid tumors, with an estimated 125,000 to 150,000 new cases diagnosed globally each year, indicating substantial market potential for an effective treatment.

Nutshell Therapeutics, founded by Professor Zhang Jian, is a pioneering biotechnology firm focused on developing small molecule drugs targeting historically difficult targets using allosteric mechanisms. The company has developed a comprehensive research and development platform, integrating both computational and laboratory methods, and has raised over $75 million from prominent venture capitalists. Through its innovative approach and extensive experience in allosteric drug development, Nutshell Therapeutics is poised to position NTS071 as a leading treatment for the p53 Y220C mutation, potentially making it a standout product among its peers.