Nutshell Therapeutics secures FDA IND clearance for NTS071, targeting p53 Y220C mutation in cancer treatment

On April 23, 2025, Nutshell Therapeutics (Shanghai) Co., Ltd. received Investigational New Drug (IND) clearance from the United States Food and Drug Administration (FDA) to initiate Phase 1 clinical trials for its leading oncology candidate, NTS071. The clearance marks a major milestone for the privately held biotechnology company as it prepares to bring its novel allosteric p53 Y220C reactivator into human testing within the United States.

NTS071 is a first-in-class oral small molecule engineered to selectively bind and stabilize the Y220C mutant variant of p53—a tumor suppressor protein mutated in a range of solid tumors. Leveraging its proprietary AI-powered drug discovery platform ALLOSTAR™, Nutshell Therapeutics developed NTS071 to address one of the most elusive targets in cancer biology using a unique allosteric mechanism.

What Is the p53 Y220C Mutation and Why Is It Significant in Cancer?

The p53 protein is often referred to as the “guardian of the genome” due to its crucial role in regulating cell cycle, DNA repair, and apoptosis. Mutations in TP53, the gene that encodes p53, are implicated in over half of all human cancers. Among these, the Y220C mutation represents a recurrent hotspot mutation found in solid tumors such as lung, breast, gastric, ovarian, pancreatic, and esophageal cancers. The Y220C mutation destabilizes the protein structure, impairing its tumor-suppressive function and facilitating oncogenesis.

Targeting the p53 Y220C mutation has long been a challenge due to the structural complexity and instability of the mutant protein. Unlike traditional inhibitors, NTS071 is an allosteric reactivator, meaning it binds to a distinct site on the protein to restore its correct folding and functionality, allowing it to bind DNA and regulate gene expression as intended.

How Does NTS071 Work and What Makes It Clinically Promising?

NTS071 stands out as a potential best-in-class therapeutic due to its novel chemical scaffold and superior pharmacological profile. Designed to be orally administered, the small molecule reactivator demonstrated picomolar-level biochemical potency—approximately 20 times more active than the leading competitor compound, PC14586. In preclinical testing, NTS071 exhibited enhanced metabolic stability in liver microsomes and hepatocytes across multiple species, including reduced in vivo clearance rates and greater oral exposure.

Moreover, NTS071 was shown to have a lower plasma protein binding rate and a higher free fraction compared to PC14586. These properties are particularly beneficial for in vivo efficacy, as they increase the amount of pharmacologically active compound available at the tumor site. NTS071 also avoids the CYP3A4 inhibition issues associated with PC14586, thereby reducing the risk of drug-drug interactions—a critical concern in oncology where combination therapies are common.

In non-clinical toxicology studies, NTS071 demonstrated a broad safety window, indicating a favourable profile for human trials. The compound’s performance in preclinical models further solidified its candidacy for IND clearance.

What Are the Results of Preclinical Studies on NTS071?

Preclinical studies using xenograft models—including both cell line-derived (CDX) and patient-derived (PDX) tumors—showed that NTS071 exhibits dose-dependent anti-tumor activity in cancers harboring the p53 Y220C mutation. These models included ovarian cancer, non-small cell lung cancer, gastric cancer, breast cancer, head and neck squamous cell carcinoma, esophageal cancer, pancreatic cancer, and bladder cancer.

These results suggest NTS071 could act as a tumor-agnostic therapeutic, offering broad-spectrum efficacy for patients whose cancers share this genetic mutation. Comparative studies revealed that NTS071 achieves equivalent or better efficacy at significantly lower doses than PC14586, reinforcing its potential to offer improved therapeutic outcomes with reduced side effects.

With an estimated 125,000 to 150,000 new cases of p53 Y220C-mutant cancers globally each year, NTS071 targets a sizeable and underserved patient population in the precision oncology market.

How Does the ALLOSTAR™ Platform Enable Advanced Drug Discovery?

Nutshell Therapeutics’ success with NTS071 is rooted in the strength of its proprietary ALLOSTAR™ drug discovery platform. By combining artificial intelligence with structural biology and medicinal chemistry, ALLOSTAR™ facilitates the identification of allosteric sites and the design of molecules that modulate protein function in non-traditional ways.

This platform has proven especially valuable in addressing “undruggable” targets like p53 Y220C, where traditional small molecule inhibitors have failed. The platform’s AI-guided screening and optimization protocols enabled Nutshell to engineer NTS071 with a high level of selectivity, potency, and developability.

Founded by leading academic scientist Professor Zhang Jian, Nutshell Therapeutics has raised more than US$75 million in venture funding to advance its portfolio of allosteric drugs. The company has built out a fully integrated R&D facility that bridges computational biology and wet lab validation, positioning itself as a frontrunner in this emerging segment of drug discovery.

What’s Next for NTS071 and Its Clinical Development Timeline?

Following FDA IND clearance, Nutshell Therapeutics plans to initiate Phase 1 clinical trials in the United States during the second half of 2025. The first-in-human study will assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of NTS071 in patients with solid tumors carrying the p53 Y220C mutation.

Given the compound’s favorable preclinical profile, industry analysts expect NTS071 to draw attention from major oncology stakeholders, including pharmaceutical companies pursuing next-generation targeted therapies. If early clinical data validate the preclinical findings, NTS071 could become a keystone treatment in tumor-agnostic precision oncology—a fast-growing space that includes landmark approvals like pembrolizumab for MSI-high tumors.

While Nutshell Therapeutics remains privately held and is not subject to public stock performance metrics, the company’s progress with NTS071 is likely to influence investor sentiment in the biotech space, particularly among funds specializing in targeted oncology and AI-driven drug discovery.

The company’s poster on NTS071, presented at the EORTC-NCI-AACR (ENA) 2024 conference, remains available online and provides detailed insights into the compound’s mechanism and comparative performance.

The FDA’s greenlighting of NTS071 positions Nutshell Therapeutics at the forefront of the race to develop precision therapies for p53-mutant cancers. With strong scientific rationale, robust preclinical validation, and a differentiated mechanism, NTS071 could offer a transformative treatment for patients who currently lack effective options. As the biotech industry increasingly turns to AI-powered platforms and allosteric modulation for the next wave of innovation, NTS071 may prove to be a landmark achievement in making previously undruggable targets treatable realities.