FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2739851992> ?p ?o ?g. }

• W2739851992 abstract "p53 gene mutations in 50% of human cancers drive the emergence of oncogenic genomes and confer resistance to anticancer drugs & apoptosis. Therefore, a pharmacological reactivation of p53 mutant proteins to their wild-type forms has emerged as an intense research area. We have shown that induction of oxidative protein modifications primarily underlie the mechanistic conversion of mutant to wt or wt-like p53 forms (Eur J Medchem 107:233, 2016; Int J Oncol 48:1426, 2016). R248W/Q DNA contact mutations in the p53 core are highly frequent and cause functional inactivation. No small molecules reactivating this p53 mutation are available. Here, we describe the design and synthesis of a small molecule KSS72 using a cell-based screening and its potency in reactivating the R248 p53 mutants. KSS72 is a non-diuretic hydrophobic analog [1-(2,3-dichloro-4-methoxyphenyl)-2-methylenebutan-1-one] of ethacrynic acid (Edecrin) obtained by removing the carboxylate side chain. KSS-72 retained the ability to bind with GSH, inhibit GSTs and induce marked redox-imbalance in tumor cells. KSS72 displayed preferential cytotoxicity (3-4 fold more cell killing) against cancer cells expressing the allele specific R248W mutation (MiaPaca-2) in comparison with the wt p53 or p53-null cancer cell lines. Further, we developed isogenic cell lines expressing the R248W and R248Q mutants in the p53-null H1299 lung cancer cells and evaluated their sensitivity towards KSS72; these models again verified the greater drug efficacy. To prove the hypothesis the higher efficacy of KSS72 stems from the reactivation of mutant p53, the conformation-specific antibodies (Pab1620 for wt and Pab420 for mutant) were employed. Immunoprecipitation and immunostaining using confocal microscopy showed that KSS72 treatment of R248W or R248Q p53-cells results in a marked reciprocal loss of mutant protein and gradual increase of wt-like protein. EMSA revealed a time-dependent restoration of DNA-binding of the mutant p53, which was accompanied by a distinct upregulation of pro-apoptotic signaling pathways mediated by PUMA, Bax, p21cip1 and MDM2 proteins. A strong G2/M arrest and significant apoptosis were observed. Other data showed that KSS72 restores the wt structure and function by covalently binding the p53R248 protein. Pharmacokinetics showed that KSS72 has excellent oral bioavailability with a half-life of 3.5 h. In MiaPaca-2 xenografts developed in nude mice, there was a marked tumor growth suppression with KSS72 as a single drug. In conclusion, KSS72 is an attractive lead compound for further development because p53 reactivation occurred without discernible organ toxicities after oral doses and a wide therapeutic window. The redox-sensitive cysteines involved in the p53 reactivation are being identified by mass spectrometry (supported by CPRIT grants RP130266 & RP170207 to KSS). Citation Format: Surendra R. Punganuru, Hanumantha Rao Madala, Kalkunte S. Srivenugopal. Induction of mild oxidative stress as a strategy for reactivation of mutant p53 proteins: KSS72, a small molecule derived from ethacrynic acid restores the biological functions of R248W/Q mutant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2570. doi:10.1158/1538-7445.AM2017-2570" @default.
• W2739851992 created "2017-08-08" @default.
• W2739851992 creator A5015226138 @default.
• W2739851992 creator A5033003394 @default.
• W2739851992 creator A5066473505 @default.
• W2739851992 date "2017-07-01" @default.
• W2739851992 modified "2023-09-25" @default.
• W2739851992 title "Abstract 2570: Induction of mild oxidative stress as a strategy for reactivation of mutant p53 proteins: KSS72, a small molecule derived from ethacrynic acid restores the biological functions of R248W/Q mutant" @default.
• W2739851992 doi "https://doi.org/10.1158/1538-7445.am2017-2570" @default.
• W2739851992 hasPublicationYear "2017" @default.
• W2739851992 type Work @default.
• W2739851992 sameAs 2739851992 @default.
• W2739851992 citedByCount "1" @default.
• W2739851992 countsByYear W27398519922023 @default.
• W2739851992 crossrefType "proceedings-article" @default.
• W2739851992 hasAuthorship W2739851992A5015226138 @default.
• W2739851992 hasAuthorship W2739851992A5033003394 @default.
• W2739851992 hasAuthorship W2739851992A5066473505 @default.
• W2739851992 hasConcept C104317684 @default.
• W2739851992 hasConcept C121608353 @default.
• W2739851992 hasConcept C143065580 @default.
• W2739851992 hasConcept C153911025 @default.
• W2739851992 hasConcept C185592680 @default.
• W2739851992 hasConcept C190283241 @default.
• W2739851992 hasConcept C2776151105 @default.
• W2739851992 hasConcept C501734568 @default.
• W2739851992 hasConcept C54355233 @default.
• W2739851992 hasConcept C55493867 @default.
• W2739851992 hasConcept C86803240 @default.
• W2739851992 hasConcept C96232424 @default.
• W2739851992 hasConceptScore W2739851992C104317684 @default.
• W2739851992 hasConceptScore W2739851992C121608353 @default.
• W2739851992 hasConceptScore W2739851992C143065580 @default.
• W2739851992 hasConceptScore W2739851992C153911025 @default.
• W2739851992 hasConceptScore W2739851992C185592680 @default.
• W2739851992 hasConceptScore W2739851992C190283241 @default.
• W2739851992 hasConceptScore W2739851992C2776151105 @default.
• W2739851992 hasConceptScore W2739851992C501734568 @default.
• W2739851992 hasConceptScore W2739851992C54355233 @default.
• W2739851992 hasConceptScore W2739851992C55493867 @default.
• W2739851992 hasConceptScore W2739851992C86803240 @default.
• W2739851992 hasConceptScore W2739851992C96232424 @default.
• W2739851992 hasLocation W27398519921 @default.
• W2739851992 hasOpenAccess W2739851992 @default.
• W2739851992 hasPrimaryLocation W27398519921 @default.
• W2739851992 hasRelatedWork W1498141812 @default.
• W2739851992 hasRelatedWork W1554604480 @default.
• W2739851992 hasRelatedWork W1973075000 @default.
• W2739851992 hasRelatedWork W2006915503 @default.
• W2739851992 hasRelatedWork W2097579843 @default.
• W2739851992 hasRelatedWork W2134507150 @default.
• W2739851992 hasRelatedWork W2134518653 @default.
• W2739851992 hasRelatedWork W2287871441 @default.
• W2739851992 hasRelatedWork W2315816673 @default.
• W2739851992 hasRelatedWork W2317436134 @default.
• W2739851992 hasRelatedWork W2326870974 @default.
• W2739851992 hasRelatedWork W2330719680 @default.
• W2739851992 hasRelatedWork W2403684948 @default.
• W2739851992 hasRelatedWork W2564547994 @default.
• W2739851992 hasRelatedWork W2565604292 @default.
• W2739851992 hasRelatedWork W2573582767 @default.
• W2739851992 hasRelatedWork W2594273972 @default.
• W2739851992 hasRelatedWork W2807273612 @default.
• W2739851992 hasRelatedWork W2886070932 @default.
• W2739851992 hasRelatedWork W2915710140 @default.
• W2739851992 isParatext "false" @default.
• W2739851992 isRetracted "false" @default.
• W2739851992 magId "2739851992" @default.
• W2739851992 workType "article" @default.