A Triple Action PROTAC for Wild-Type p53 Cancer Therapy

ABSTRACT: Multiagent chemotherapy remains a cornerstone of cancer treatment but the side effects of each drug component can heighten toxicity and the pharmacologic challenges in achieving simultaneous cellular delivery can reduce efficacy and promote resistance. To address these limitations, we developed a Triple Action Proteolysis Targeting Chimera (TAPTAC) that targets three oncogenic mechanisms at once to maximally reactivate apoptosis in cancer. Our prototype, TAPTAC1, is a stapled peptide-small molecule chimera that transforms oncogenic HDM2 into a tumor suppressor by switching its mode of action from degrading p53 to a selected cancer target and by maximizing the synergistic p53 surge through further blockade of HDMX, another negative regulator of p53. TAPTAC1 is effective across a broad spectrum of cancers, with specificity of action driven by wild-type (WT) p53 status and pathway co-dependencies, as evidenced by multi-omics analyses. Importantly, TAPTAC1 activity is superior to combination treatment with the individual drug components and a small molecule PROTAC that targets HDM2 and BET proteins but not HDMX. Pharmacokinetic analyses guided dose-selection and in vivo testing demonstrated that TAPTAC1 was effective in mouse models of human osteosarcoma and leukemia, without evidence of gross toxicity. Quantitative proteomics confirmed elimination of BET proteins and robust p53 pathway activation in vitro and in vivo. Given the numerous drug modalities that depend on and synergize with p53 reactivation, and the preservation of WT p53 in ~90% of pediatric and ~50% of adult cancers, TAPTACs provide a drug development platform with the potential to achieve multiagent activity as single agents, overcoming limitations in the pharmacology, toxicology, efficacy, and clinical trial logistics of anti-cancer drug combinations.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Joao Paulo  

LAB HEAD: Loren D.Walensky

PROVIDER: PXD060332 | Pride | 2026-01-12

REPOSITORIES: Pride