On May 4, 2025 Nutshell Therapeutics ( Shanghai ) Co., LTD. reported to have received IND clearance from the FDA to initiate Phase 1 clinical trial in the United States for its NTS071, a novel small molecule allosteric reactivator targeting p53 Y220C mutation (Press release, Nutshell Therapeutics, MAY 4, 2025, View Source [SID1234652483]).
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NTS071 is an oral small molecule allosteric reactivator targeting p53 Y220C with a novel scaffold. It selectively binds to the p53 Y220C mutant protein, improving its thermal stability, thereby enhancing the mutant protein’s ability to bind with DNA and restoring its transcriptional activity as well as tumor-suppressing function.
NTS071 was discovered by leveraging Nutshell’s proprietary AI driven allosteric small molecule drug discovery platform ALLOSTAR. NTS071 demonstrated potential Best-in-Class preclinical properties for its target. NTS071 achieved a picomolar-level biochemical activity which is 20 folds more potent than the competitive compound PC14586. Additionally, NTS071 shows better stability in both liver microsomes and hepatocytes across different species and exhibits lower in vivo clearance rates and higher oral exposure s in preclinical PK studies across all tested species compared to PC14586. NTS071 has relatively lower plasma protein binding and higher free fraction than PC14586, which is beneficial for in vivo efficacy. NTS071 also addresses the CYP3A4 inhibition issue of PC14586, presenting lower risks for potential drug – drug interactions. NTS071 further displays a large safety window by exhibiting an overall good safety profile in non-clinical toxicology studies.
NTS071 exhibited dose-dependent in vivo anti-tumor activity in multiple CDX and PDX models harboring p53 Y220C mutation, spanning a number of different cancer types, including ovarian cancer, lung cancer, gastric cancer, breast cancer, head and neck cancer, esophageal cancer, pancreatic cancer, and bladder cancer, etc. Therefore, NTS071 has the potential to be a tumor-agnostic therapy for patients carrying p53 Y220C mutation. Compared to PC14586, NTS071 has shown significantly lower effective doses or better efficacy at the same dose level in all comparative preclinical in vivo studies, implying that NTS071 may overcome the limitation of its competitor that has a higher dose requirement, thereby potentially achieving better therapeutic effects. NTS071 is anticipated to initiate Phase 1 clinical trial in second half of 2025 and expected to benefit patients with solid tumors harboring this mutation.
p53 Y220C mutation is widespread in various solid tumors. Studies show that there are 125,000 to 150,000 new cases worldwide annually, representing a significant market potential. Enriched with years of accumulated experience with its proprietary computation-based allosteric drug development technology and breakthrough innovation capabilities at Nutshell Therapeutics, NTS071 has the potential to stand out among peer products and become the most competitive drug molecule for this target.
The NTS071 Poster presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) 2024 conference can be accessed here: View Source