Small molecule activators of the p53 response

Abstract

Drugging the p53 pathway has been a goal for both academics and pharmaceutical companies since the designation of p53 as the ‘guardian of the genome’. Through growing understanding of p53 biology, we can see multiple routes for activation of both wild-type p53 function and restoration of mutant p53. In this review, we focus on small molecules that activate wild-type p53 and that do so in a non-genotoxic manner. In particular, we will describe potential approaches to targeting proteins that alter p53 stability and function through posttranslational modification, affect p53’s subcellular localization, or target RNA synthesis or the synthesis of ribonucleotides. The plethora of pathways for exploitation of p53, as well as the wide-ranging response to p53 activation, makes it an attractive target for anti-cancer therapy.

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX‐5461 on pulmonary arterial hypertension and associated vascular remodelling

“…Pol I inhibitors have been recognized to be a novel strategy to activate the p53 pathway (Ladds & Lain, 2019) and both genetic deletion and pharmacological inhibition of p53 aggravate the development of PAH in animal models (Jacquin et al, 2015;Mizuno et al, 2011). Further supporting our current results, Mouraret et al (2013) have shown that nutlin-3, a small molecule that blocks the p53 degrading activity of the ubiquitin ligase MDM2, exhibits potent therapeutic effects against experimental pulmonary hypertension and suppresses pulmonary arterial remodelling.…”

Gain-of-function mutant p53 in cancer progression and therapy

“…The first is to target mutp53 directly by restoration of the wild-type tumor-suppressive function of p53 or deprivation of mutp53 through inducing its degradation. The second is to target specific mutp53-binding proteins or critical downstream signaling pathways of mutp53 to inhibit mutp53 GOF activities ( Blandino and Di Agostino, 2018 ; Ladds and Lain, 2019 ; Zhou et al., 2019 ).…”

Potency and Selectivity Optimization of Tryptophanol‐Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer

“…In the past 20 years, several chemical libraries were developed with the aim of inhibiting MDM2 and p53 interaction and currently only one small molecule, HDM201, has undertaken clinical development for colorectal cancer in combination therapies [24,25] …”