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AACR 2025: Orally Bioavailable RIPTAC Therapeutic Targets p53-Y220C Mutant Tumors for Selective Cancer Cell Death
Key Takeaways
- RIPTAC therapeutics target the p53-Y220C mutant, forming a ternary complex that selectively induces cancer cell death by exploiting tumor-specific vulnerabilities.
- The RIPTAC platform enhances tumor selectivity by reactivating p53 and disrupting essential protein functions, offering superior efficacy over traditional therapies.
A novel orally bioavailable RIPTAC therapeutic targeting the p53-Y220C mutation demonstrates selective cancer cell killing by inducing proximity between mutant p53 and an essential protein, offering a promising new strategy for treating historically untreatable tumors.
The tumor suppressor p53 remains one of the most studied proteins in oncology, yet also one of the most elusive in terms of effective therapeutic targeting. Mutated in over 50% of human cancers, p53 plays a pivotal role in maintaining genomic integrity by regulating apoptosis, cell cycle arrest, and DNA repair in response to cellular stress. Unfortunately, the structural complexity and intracellular localization of p53, particularly its DNA-binding domain, have rendered it historically untreatable.
However, a new class of small molecules called Regulated Induced Proximity Targeting Chimeras (RIPTAC) therapeutics is beginning to change that paradigm. Presented in a poster at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago, Illinois, Lupey-Green et al showed they were able to develop an orally bioavailable RIPTAC compound specifically targeting the p53-Y220C mutant tumor.
Microscopic view of cancer cells. Image Credit: © Ilja - stock.adobe.com
“The RIPTAC platform is a unique strategy that allows tumor specificity in targeting mutant p53 via a heterobifunctional small molecule, which consists of 2 ligands connected by a linker, and in this case 1 ligand binds to mutant p53 and the other ligand binds to a tumor specific protein,” said Matthew Lei, PharmD, BCOP, clinical pharmacy specialist – lymphoma at Massachusetts General Hospital in Boston and editorial advisory board member for Pharmacy Practice in Focus: Oncology, to Pharmacy Times.
The Y220C missense mutation is structurally unique variant that occurs in approximately 1% of human cancers, and 20,000 US patients, annually. The p53-Y220C mutant tumor is a conformational defect that results in reduced DNA-binding capacity and a loss of tumor suppressor function. While some pharmacological chaperones have demonstrated the ability to stabilize p53-Y220C, effectively reactivating the protein to some degree, the clinical benefit of these compounds has been limited. The mechanism of these pharmacological chaperones in prior studies have been shown to be largely restorative, attempting to return p53 to its wild-type function, but they may not produce sufficient or sustained tumor cell death when used as monotherapy. Recognizing these limitations, Lupey-Green et al aimed to build on this foundation by applying their RIPTAC platform to both exploit and enhance the reactivation phenotype.
RIPTACs contain 1 ligand that binds a tumor-specific target protein (TP), such as p53-Y220C, and 1 ligand that binds an essential protein (EP), which is indispensable for cell survival. Upon binding, the RIPTAC molecule induces the formation of a ternary complex, bringing the mutant TP into close proximity with the EP. This engineered protein-protein interaction can lead to functional inactivation of the EP in tumor cells, causing selective cancer cell death while sparing normal tissue that lacks the tumor-specific protein. This strategy can enhance tumor selectivity and leverages a dual mechanism of action—both reactivating p53 and functionally disrupting a vital cellular process.
The results of the study presented by Lupey-Green et al shows compelling preclinical evidence of efficacy and selectivity for the p53-Y220C–targeting RIPTAC. The compound forms a stable ternary complex between p53-Y220C and an undisclosed pan-essential protein, which the investigators have identified as a critical factor for the survival of cancer cells harboring the mutation. In vitro studies demonstrated that treatment with this RIPTAC led to potent anti-proliferative effects in p53-Y220C–expressing cell lines, but not in cells lacking the mutation. This selectivity is a significant advantage over conventional chemotherapy and even many targeted therapies, which often impact healthy dividing cells and cause systemic toxicity.
Compared to previously studied pharmacological chaperones, the RIPTAC compound exhibited superior efficacy in promoting apoptosis and reducing cell viability. The mechanistic advantage lies in its ability to not only restore p53’s conformation but also to modulate downstream protein dynamics in a ternary complex. Importantly, modulation of the essential protein in the complex was shown to be tumor-selective and dependent on the presence of the p53-Y220C mutation, further underscoring the precision of this approach. These effects were confirmed through pharmacodynamic (PD) assays demonstrating essential protein loss-of-function and downstream apoptotic signaling.
Another noteworthy advancement is the compound’s oral bioavailability. Oral therapeutics provide substantial benefits for patients in terms of administration, especially in comparison to intravenously administered biologics or chemotherapeutics. According to Lupey-Green et al, early pharmacokinetic/PD studies are ongoing in cell line-derived xenograft models of p53-Y220C driven tumors to further validate the in vivo activity, safety, and bioavailability of the RIPTAC candidate.
The development of this RIPTAC therapeutic is significant not only for the p53-Y220C mutation but also as a proof-of-concept for targeting other historically untreatable mutations in cancer. By shifting the therapeutic strategy from restoring protein function to hijacking cancer-specific vulnerabilities through induced proximity, this platform provides therapeutic advantages. This approach also opens the door for multiplexed targeting—whereby RIPTACs could simultaneously modulate multiple proteins within a tumor-selective context—potentially overcoming issues of resistance and heterogeneity.
“The efforts to develop and bring a KRAS inhibitor to the clinic took nearly 40 years,” Lei said to Pharmacy Times. “Now sights are set on bringing therapies to the clinic that target mutant p53 and restore its wild-type conformation.”
