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Ref Type Journal Article
PMID (31405179)
Authors Gomes S, Bosco B, Loureiro JB, Ramos H, Raimundo L, Soares J, Nazareth N, Barcherini V, Domingues L, Oliveira C, Bisio A, Piazza S, Bauer MR, Brás JP, Almeida MI, Gomes C, Reis F, Fersht AR, Inga A, Santos MMM, Saraiva L
Title SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma.
Journal Cancers
Vol 11
Issue 8
Date 2019 Aug 10
URL
Abstract Text Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
SLMP53-2 p53 Activator 11 SLMP53-2 is a compound that reactivates mutant Tp53, potentially resulting in decreased tumor cell growth (PMID: 31405179).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 Y220C breast ductal carcinoma sensitive SLMP53-2 Preclinical - Cell culture Actionable In a preclinical study, SLMP53-2 treatment inhibited growth of a breast ductal carcinoma cell line harboring TP53 Y220C and resulted in increased expression of the Tp53 targets MDM2, p21, and KILLER and decreased expression of Survivin and VEGF in culture (PMID: 31405179). 31405179
TP53 G245S lung non-small cell carcinoma sensitive SLMP53-2 Preclinical - Cell culture Actionable In a preclinical study, SLMP53-2 inhibited growth of a non-small cell lung carcinoma cell line expressing TP53 G245S in culture (PMID: 31405179). 31405179
TP53 Y220C hepatocellular carcinoma sensitive SLMP53-2 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with SLMP53-2 induced cell-cycle arrest and apoptosis and inhibited growth, and resulted in restored Tp53 transcriptional activity in a hepatocellular carcinoma cell line harboring TP53 Y220C in culture, and inhibited tumor growth in xenograft models (PMID: 31405179). 31405179
TP53 Y220C hepatocellular carcinoma sensitive SLMP53-2 + Sorafenib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SLMP53-2 and Nexavar (sorafenib) inhibited growth of a hepatocellular carcinoma cell line harboring TP53 Y220C in culture, and resulted in increased inhibition compared to Nexavar (sorafenib) alone (PMID: 31405179). 31405179
TP53 Y220C lung non-small cell carcinoma sensitive SLMP53-2 Preclinical - Cell culture Actionable In a preclinical study, SLMP53-2 inhibited growth of a non-small cell lung carcinoma cell line expressing TP53 Y220C in culture (PMID: 31405179). 31405179
TP53 R175H lung non-small cell carcinoma sensitive SLMP53-2 Preclinical - Cell culture Actionable In a preclinical study, SLMP53-2 inhibited growth of a non-small cell lung carcinoma cell line expressing TP53 R175H in culture (PMID: 31405179). 31405179