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Discovery and development of new small-molecule immune system modulators

2019-12Doctoral thesis Restricted access
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorGuedes, Rita Alexandra do Nascimento Cardoso
dc.contributor.advisorFerreira, Helena Isabel Fialho Florindo Roque
dc.contributor.advisorSalvador, Jorge António Ribeiro
dc.contributor.authorAcúrcio, Rita C
dc.date.accessioned2020-04-08T13:58:09Z
dc.date.available2020-04-08T13:58:09Z
dc.date.issued2019-12
dc.date.submitted2019-10
dc.description.abstractModulation of immune modulatory pathways has emerged as one of the most successful and explored approaches for cancer immunotherapy. Current therapeutics include monoclonal antibodies, which have shown impressive clinical outcomes in the treatment of several types of tumors. However, low response rate, patient acquired resistance and induction of severe immune-related adverse effects represent critical drawbacks. To overcome these limitations, complementary strategies that inhibit tumor immunosuppressive pathways and enhance immunity are urgently needed. We hypothesized that inhibition of PD-1/PD-L1 interaction, for immunosuppression blockade, could be improved by the development of immune modulatory small molecules. For this purpose, we developed a computer-assisted drug design approach that allowed the identification of potential PD-1/PD-L1 small-molecule inhibitors. These potential hits were confirmed as true hits by in vitro and ex vivo assessment of its antitumor immune response. The compounds identified were able to activate T cell function by increasing tumor-associated antigen recognition, processing and presentation to effector T cells. The use of computational-aided drug design tools was decisive to accelerate the identification of new immune small molecules modulators which, certainly, will play a key role in the next generation of cancer immunotherapy approaches. Hits were identified by a structure based virtual screening campaign based on molecular docking. In addition to hit discovery, these methods were essential in providing a strong structural elucidation. Over biochemical and in vitro studies three PD-1/PD-L1 small-molecule inhibitors by direct PD-L1-binding were identified at nanomolar scale. Two different types of cancer, a highly immunogenic (melanoma) and a traditionally non-responder to immune checkpoint modulation (breast cancer) were studied in vitro. Finally, co-culture experiments were developed and the treatment with the identified inhibitors led to T cell activation and antigen-specific cytotoxic T-cell activity against melanoma cells ex vivo. Altogether, these findings reveal important aspects on the use of small molecules as immune checkpoint modulators, as well as their effect on the modulation of tumor-infiltrating immune cells. This approach offers numerous advantages over the use of monoclonal antibodies, predominantly on pharmacokinetics properties. In addition, they represent a more affordable and accessible alternative. Therefore, small-molecule immune system modulators emerge as a potential strategy to improve clinical outcomes of cancer treatment.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2020-03-25T16:01:28Z No. of bitstreams: 1 ULSD734234_td_Ana_Acurcio.pdf: 1449375 bytes, checksum: 59812441530a3826b2afebee2fe3c1ab (MD5)en
dc.description.provenanceMade available in DSpace on 2020-04-08T13:58:09Z (GMT). No. of bitstreams: 1 ULSD734234_td_Ana_Acurcio.pdf: 1449375 bytes, checksum: 59812441530a3826b2afebee2fe3c1ab (MD5) Previous issue date: 2019-12en
dc.identifier.tid101521936pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/42786
dc.language.isoengpt_PT
dc.relationDiscovery and development of novel small molecule immune system modulators
dc.relationResearch Institute for Medicines
dc.relationModulation of melanoma-stroma interactions using a rationally-designed nanomedicine combining BRAFi-, MEKi- and immune-therapies
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.subjectCancer immunotherapypt_PT
dc.subjectimmune checkpoint inhibitorpt_PT
dc.subjectsmall-molecule inhibitorspt_PT
dc.subjectPD-L1pt_PT
dc.subjectvirtual screeningpt_PT
dc.titleDiscovery and development of new small-molecule immune system modulatorspt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitleDiscovery and development of novel small molecule immune system modulators
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleModulation of melanoma-stroma interactions using a rationally-designed nanomedicine combining BRAFi-, MEKi- and immune-therapies
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128238%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQEQ-MED%2F7042%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FDTP%2F04138%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/ENMed%2F0051%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
oaire.fundingStream9471 - RIDTI
person.familyNamede Carvalho Acúrcio
person.givenNameAna Rita
person.identifier.ciencia-id8F1C-FAF0-2051
person.identifier.orcid0000-0003-3412-1903
person.identifier.scopus-author-id56154070500
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.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
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.rightsrestrictedAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isAuthorOfPublication63aca2ea-a095-4eaa-8f23-07c305ae5516
relation.isAuthorOfPublication.latestForDiscovery63aca2ea-a095-4eaa-8f23-07c305ae5516
relation.isProjectOfPublication5cc13cdb-a24e-4708-b7aa-6e4e1b4f10d8
relation.isProjectOfPublication447d01cf-d361-45b5-b65f-1af81dfc6eb6
relation.isProjectOfPublicationf7ed2a0a-c67e-4c12-ad63-b550724e24bf
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relation.isProjectOfPublication.latestForDiscovery447d01cf-d361-45b5-b65f-1af81dfc6eb6
thesis.degree.nameTese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2019pt_PT

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