A selective p53 activator and anticancer agent to improve colorectal cancer therapy.

Helena Ramos,Bartolomeo Bosco,Liliana Raimundo,Joana Silva,Ana Teresa Rajado,Célia Gomes,Alberto Inga,Flávio Reis,Silvano Piazza,Petr Chlapek,Juliana Calheiros,Claúdia Nunes ,Filipe Almeida Monteiro ,Petr Vlček ,Pavel Fabián ,Renata Veselská ,Teresa M V D Pinho E Melo ,Lucı́lia Domingues ,Alexandra Carvalho ,Maria I L Soares ,Filipa S Reis ,Lucı́lia Saraiva

doi:10.1016/j.celrep.2021.108982

Abstract

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and invitro and invivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.

Highlights

Colorectal cancer (CRC) is currently the third most common cancer type and one of the leading causes of death worldwide (International Agency for Research on Cancer and World Health Organization, 2019)
MANIO displays p53-dependent growth-inhibitory effect in human cancer cells, inducing cell-cycle arrest and apoptosis in CRC cells In an attempt to identify new effective p53-activating agents with antitumor activity, the antiproliferative effect of a small chemical library of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles was investigated in a panel of human cancer cells with different p53 status
Results clearly demonstrated that MANIO had a p53-dependent antiproliferative activity against cancer cells, with significantly lower IC50 values in cancer cells expressing WTp53 (0.20–0.97 mM) or mutp53 (0.088–6.27 mM), compared to p53 null cells (26.20– 48.25 mM) (Figures 1B, 1C, and S1A)

Summary

Introduction

Colorectal cancer (CRC) is currently the third most common cancer type and one of the leading causes of death worldwide (International Agency for Research on Cancer and World Health Organization, 2019). The increasing incidence of early-onset cases, due to Western diet and lifestyle, has emphasized the concern of the clinical community regarding CRC (Dekker et al, 2019; Araghi et al, 2019). The commonly associated high mortality and therapeutic resistance have exposed the fragility of its treatment (Dekker et al, 2019). Considerable advances in pathophysiological understanding of CRC have paved the way to an array of targeted therapies for its personalized treatment. The disruption of the p53 pathway, mostly by TP53 mutation or p53 inhibition through interaction with negative regulators, is a major pathological event in local and advanced CRC (Li et al, 2015). The tumor suppressor protein p53 is the central hub of a complex molecular network, coordinating major

Results

Discussion

Conclusion