Abstract 7092: Highly potent and mutant-selective p53 Y220C reactivators with best-in-class potential

Abstract Background: The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates genes involved in DNA repair, cell cycle arrest, senescence, and apoptosis. TP53 is the most frequently altered tumor suppressor gene with mutations occurring in over 50% of human cancers. TP53 mutations result in a loss of function, rendering cells incapable of responding to a variety of cellular stresses, making them susceptible to tumorigenesis. The Y220C hotspot mutation accounts for 1.8% of all p53 mutations, occurring in ∼1% of all solid tumors. p53 Y220C is a structural mutation that causes destabilization of the p53 protein. Small molecules that bind to a pocket formed by the Y220C mutation, but absent in the p53 wild-type protein, can stabilize the protein to restore normal function. Rezatapopt (PC14586) is the first p53 Y220C reactivator to enter clinical trials, where it is showing clinical benefit. However, because this molecule has modest potency, its efficacy may be limited by insufficient p53 reactivation despite a high RP2D (2000 mg QD), particularly in KRAS mutant patients. Materials and Methods: Antares’s p53 Y220C reactivators were evaluated biochemically in SPR binding and thermal shift assays. Cellular activity was assessed in target engagement, target gene expression and cell proliferation assays across a panel of p53 Y220C mutant cell lines. Additionally, chromatin binding and target gene expression conferred by p53 Y220C reactivation were analyzed by ChIP-seq and RNA-seq. Finally, the in vivo efficacy was studied in several human CDX and PDX p53 Y220C models. Results: Antares’s orally bioavailable p53 Y220C reactivators demonstrated a ≥10-fold improvement in in vitro potency over rezatapopt in target engagement, ChIP-seq and RNA-seq assays, with corresponding potency improvements in cell proliferation assays across a panel of p53 Y220C mutant cell lines. In vivo, these compounds were effective in inhibiting tumor growth in multiple p53 Y220C CDX models at a significantly lower dose than rezatapopt. Importantly, these p53 reactivators exhibit a marked improvement in activity in a KRAS mutant model, both in vitro and in vivo. Conclusions: The significantly improved potency of the novel p53 reactivators described here offers the opportunity to restore p53 function in less sensitive patient populations and meaningfully improve upon the clinical response profile of rezatapopt. Citation Format: Chiou-Hong Lin, Benjamin C. Milgram, Brendon Ladd, Weixue Wang, John P. Vu, Jun Jacob Hu, Yemin Lan, Keyur Gada, Heidi Koldsoe, Stephanie M. Reeve, Robert Hicklin, Mint Sirisawad, Brendan J. Hilbert, Jack A. Henderson, Simon A. Roberts, Gregory Kryukov, Hsu-Ping Kuo, Natasja Brooijmans, Angel Guzman-Perez, Darrin D. Stuart, Erica L. Jackson. Highly potent and mutant-selective p53 Y220C reactivators with best-in-class potential abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7092.