Abstract LB428: An orally bioavailable RIPTAC™ therapeutic for p53 Y220C mutant tumors

Abstract The p53 tumor suppressor protein is the most frequently mutated gene in human cancers. Despite decades of effort, this transcription factor is considered a historically “undruggable” target. Mutations in the p53 DNA binding domain (DBD) result in either the inability of p53 to bind DNA and exert its tumor suppressor function, or in conformational instability leading to aggregation of the mutant protein. The Y220C missense mutation encodes a structural p53 mutant that occurs in approximately 1% of human cancers, or 20,000 US patients, annually. In recent years, small molecule chaperones have been developed that selectively bind the p53Y220C mutant and stabilize it in the wild-type conformation. While these compounds restore tumor suppressor activity of p53, it is unknown whether this reactivation alone is sufficient to drive clinical efficacy. Targeted approaches that build upon this reactivation phenotype or in other ways leverage its tumor-specific expression may provide superior therapeutic options for patients with tumors harboring the Y220C mutation. Regulated Induced Proximity Targeting Chimeras or RIPTAC™ Therapeutics are a new class of heterobifunctional small molecules developed by Halda Therapeutics. RIPTACs work by recruiting a tumor-specific target protein (TP) into an intracellular ternary complex with a pan-essential protein (EP) necessary for cell survival, resulting in selective cell death. We have leveraged our technology platform to develop a RIPTAC that complexes p53Y220C with an undisclosed EP to selectively kill tumor cells that express this mutant protein. The p53Y220C RIPTAC exhibits enhanced antiproliferative activity compared to reported p53 pharmacological chaperones, and unlike these compounds is a potent inducer of apoptosis across a panel of p53Y220C mutant cells lines. Trimer formation induced by the RIPTAC causes substantial tumor-selective EP modulation as well as a significantly more pronounced p53 reactivation phenotype compared to the p53Y220C binding ligand alone. Together, these mechanisms of action downstream of the trimer complex highlight a unique mode of action that may overcome potential limitations of current p53Y220C reactivators. Moreover, we have demonstrated that the RIPTAC is orally bioavailable and in vivo studies investigating PD modulation and efficacy in a p53Y220C tumor model are ongoing. Taken together, these data support advancing the p53Y220C RIPTAC program toward the clinic as a potential therapeutic option for patients with tumors that harbor this historically undruggable mutation. Citation Format: Lena N. Lupey-Green, Louise C. Giffin, Nilesh Zaware, Chris D. Forbes, Amit Bhardwaj, Aiyana Ward, Madeline P. King, Andrew McGovern, Abigail Hundt, Rebecca Stronk, Samantha Fasciano, Michael B. Martin, Kelli Jones, Keely Cooney-Walsh, Katia Howard, Cassidy Marshall, Kyle Bassoli, Rebekka Chenard, Kyle J. Eastman, Kanak Raina, Katherine J. Kayser-Bricker. An orally bioavailable RIPTAC™ therapeutic for p53 Y220C mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB428.