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Design, synthesis and biological evaluation of novel p53 activators by targeting p53 protein-protein interactions

2021-10Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Médicas::Ciências da Saúdept_PT
dc.contributor.advisorSantos, Maria Manuel Duque Vieira Marques dos
dc.contributor.advisorConway, Stuart John
dc.contributor.advisorRodrigues, Cecília Maria Pereira
dc.contributor.authorEspadinha, Margarida
dc.date.accessioned2022-10-03T17:17:09Z
dc.date.available2024-11-01T01:30:56Z
dc.date.issued2021-10
dc.date.submitted2021-07
dc.description.abstractThe p53 protein, also known as the “guardian of the genome”, has an important role in the tumor suppression and regulation of cell processes. The majority of human cancers show inactivation of the p53 pathway. This perturbation can occur either by negative regulation, either by mutation or deletion of its gene. In tumors harboring wt p53, the MDM2 and MDMX homologous proteins are the main contributors for suppressing the p53 functions. In the last years, the development of p53-MDM2 PPI small molecule inhibitors has been one of the most popular approaches to reactivate wt p53, with eight clinical candidates under evaluation. However, it is now considered that, to achieve a full p53 reactivation, a dual inhibition of MDM2 and MDMX is required. Until today, there is no dual small molecule inhibitors of p53-MDM2/X PPIs in clinical trials. In the last years, our group has been working on the design of five-membered spirooxindoles to develop novel anticancer agents. This work explores the design of the spiropyrazoline oxindole family to act as MDM2/X dual inhibitors. Here, we report an in silico-guided design, synthetic optimization, and biological evaluation of two libraries of spiropyrazoline oxindoles. p53 also interacts with CREBBP. The inhibition of the p53-CREBBP PPI in certain biological circumstances can result in the p53 stabilization. For this purpose, PROTAC technology that allows to degrade the CREBBP protein was implemented, based on a lead CREBBP ligand developed in the Conway group. Also, a yeast target-based screening of enantiopure tryptophanol derivatives led to the identification of dual p53-MDM2/X inhibitors, which were further optimized to compounds DIMP53-1, SYNAP and SLMP53-1, the last being also a mut p53 reactivator. To better understand the mechanism of action of this chemical family, in particular of SLMP53-1, two types of chemical probes were prepared, and preliminary in vitro cell assays were performed to evaluate their potential in future applications. Also, the preliminary biological and photocrosslinking results for SLMP53-1 photoaffinity-based probe showed its potential for the biological target profile of this compound. Overall, this PhD thesis has provided valuable insights in the development of p53 activators.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2022-09-12T14:35:17Z No. of bitstreams: 1 scnd739134_td_Margarida_Espadinha.pdf: 6043746 bytes, checksum: f84d5758dd1cca41c41b9cd83b155c2e (MD5)en
dc.description.provenanceMade available in DSpace on 2022-10-03T17:17:09Z (GMT). No. of bitstreams: 1 scnd739134_td_Margarida_Espadinha.pdf: 6043746 bytes, checksum: f84d5758dd1cca41c41b9cd83b155c2e (MD5) Previous issue date: 2021-10en
dc.identifier.tid101555113pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/54685
dc.language.isoengpt_PT
dc.relationDesign, synthesis and biological evaluation of novel p53 activators by targeting p53 protein-protein interactions
dc.subjectanticancer therapypt_PT
dc.subjectCREBBPpt_PT
dc.subjectMDM2pt_PT
dc.subjectMDMXpt_PT
dc.subjectspiropyrazoline oxindolespt_PT
dc.subjectprobespt_PT
dc.subjectPROTACpt_PT
dc.subjectprotein-protein interactionpt_PT
dc.subjectp53pt_PT
dc.titleDesign, synthesis and biological evaluation of novel p53 activators by targeting p53 protein-protein interactionspt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/117931/2016
oaire.awardNumberPTDC/QUI-QOR/29664/2017
oaire.awardNumberPTDC/QUI-QOR/1304/2020
oaire.awardTitleDesign, synthesis and biological evaluation of novel p53 activators by targeting p53 protein-protein interactions
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F117931%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-QOR%2F29664%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-QOR%2F1304%2F2020/PT
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
person.familyNameFlorindo Espadinha
person.givenNameMargarida Leonor
person.identifier.ciencia-idC410-5BE1-0E70
person.identifier.orcid0000-0002-7053-0475
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isAuthorOfPublication532ebbb3-b377-40b3-8286-8a515ab43024
relation.isAuthorOfPublication.latestForDiscovery532ebbb3-b377-40b3-8286-8a515ab43024
relation.isProjectOfPublication67634912-6d86-4d9e-b912-389425fd7165
relation.isProjectOfPublication06406681-cad8-4317-bf19-dd7ce2402c8d
relation.isProjectOfPublicatione2a4085b-1bb1-4d3c-84e3-36f380c0f7cf
relation.isProjectOfPublication.latestForDiscovery67634912-6d86-4d9e-b912-389425fd7165
thesis.degree.nameTese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2021pt_PT

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