Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancers	11	8	2019 Aug 10		Cancers (Basel)

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
SLMP53-2	SLMP53-2	5	0

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 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
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 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	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 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