Broad-spectrum rescue compounds for structural p53 mutations: perspective on ‘Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site’

摘要

Precision medicine targeting gene mutations holds the promise of changing the landscape of cancer care and prognosis, but currently approved drugs in this category are efficacious in only a very small percentage of all cancer patients (Tannock and Hickman, 2016). TP53, encoding the tumor suppressor and transcription factor p53, is the most frequently mutated gene in human cancers (Joerger and Fersht, 2016; Sabapathy and Lane, 2018; Levine, 2019). Pharmacologically rescuing mutant p53 by restoring wild-type function could therefore potentially be widely applicable in cancer treatment and is considered to be a holy grail of cancer research (Joerger and Fersht, 2010). Indeed, at least 17 compounds that can rescue mutant p53 variants were reported by 2018 (Sabapathy and Lane, 2018). Unfortunately, p53 mutations still remain therapeutically nonactionable due to challenges such as heterogeneous mechanisms of inactivation by different mutations and the absence of obvious targetable drug-binding pockets (except Y220C mutant). In a recent publication (Chen et al., 2021), we reported the identification of small-molecule compounds that rescue a broad class of p53 mutations. Notably, these include arsenic trioxide (ATO), which is used to treat acute promyelocytic leukemia (de Thé et al., 2017). The study differentiates itself from previous reports in: (i) rescuing mutant p53 at striking levels when benchmarked against previously reported rescue compounds; (ii) providing a structural mechanism, wherein the arsenic atom binds to a cryptic allosteric site connecting the loop–sheet–helix (LSH) motif with the β-sandwich skeleton to increase the thermostability of mutant p53; (iii) offering a largely defined spectrum of applicable p53 mutations—the structural mutations that compromise the wild-type structure of p53 and collectively account for more than half of all clinically relevant p53 alterations.