Small-molecule modulation of p53 protein-protein interactions
Small-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been sh...
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Veröffentlicht in: | Biological chemistry 2020-07, Vol.401 (8), p.921-931 |
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description | Small-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction. |
doi_str_mv | 10.1515/hsz-2019-0405 |
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The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. 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The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction.</description><subject>14-3-3</subject><subject>14-3-3 protein</subject><subject>14-3-3-p53 protein-protein interaction stabilization</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Forskolin</subject><subject>MDM2 protein</subject><subject>MDM2-p53 protein-protein interaction inhibition</subject><subject>Modulation</subject><subject>Oncology</subject><subject>p53</subject><subject>p53 Protein</subject><subject>Pharmaceutical industry</subject><subject>Protein interaction</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><issn>1431-6730</issn><issn>1437-4315</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNptkD1PwzAQhi0EoqUwsqJIzAZfznESCQZU8SVVYgBmy0lsSJXExU6Eyq_HaQssLHc3PHrv7iHkFNgFJJBcvvsvGjPIKeMs2SNT4JhSjpDsb2agIkU2IUfeLxljGeN4SCYYM54LjlNy_dyqpqGtbXQ5NDpqbTU0qq9tF1kTrRKMVs72uu7orkd112unyhHxx-TAqMbrk12fkde725f5A1083T_Obxa0xJT3m8qzIhdaZUKh0kXGU6wwFyw2mECBgAZNxUVuMIsNMAhHIzdJxTOtNM7I-TY3HPExaN_LpR1cF1bKmMciFRD-ChTdUqWz3jtt5MrVrXJrCUyOsmSQJUdZcpQV-LNd6lC0uvqlf-wE4GoLfKomPF3pNzesw_C3_d9gziDLY8Bvrih3jA</recordid><startdate>20200728</startdate><enddate>20200728</enddate><creator>Kuusk, Ave</creator><creator>Boyd, Helen</creator><creator>Chen, Hongming</creator><creator>Ottmann, Christian</creator><general>De Gruyter</general><general>Walter de Gruyter GmbH</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0001-7315-0315</orcidid></search><sort><creationdate>20200728</creationdate><title>Small-molecule modulation of p53 protein-protein interactions</title><author>Kuusk, Ave ; 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The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. 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subjects | 14-3-3 14-3-3 protein 14-3-3-p53 protein-protein interaction stabilization Deoxyribonucleic acid DNA Forskolin MDM2 protein MDM2-p53 protein-protein interaction inhibition Modulation Oncology p53 p53 Protein Pharmaceutical industry Protein interaction Proteins Rapamycin Tumor suppressor genes Tumors |
title | Small-molecule modulation of p53 protein-protein interactions |
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