Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ
Abstract Targeting the PI3K isoform p110δ against B cell malignancies is at the mainstay of PI3K inhibitor (PI3Ki) development. Therefore, we generated isogenic cell lines, which express wild type or mutant p110δ, for assessing the potency, isoform-selectivity and molecular interactions of various P...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-04921-z |
| _version_ | 1797806575417556992 |
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| author | Floyd Hassenrück Maria Farina-Morillas Lars Neumann Francesco Landini Stuart James Blakemore Mina Rabipour Juan Raul Alvarez-Idaboy Christian P. Pallasch Michael Hallek Rocio Rebollido-Rios Günter Krause |
| author_facet | Floyd Hassenrück Maria Farina-Morillas Lars Neumann Francesco Landini Stuart James Blakemore Mina Rabipour Juan Raul Alvarez-Idaboy Christian P. Pallasch Michael Hallek Rocio Rebollido-Rios Günter Krause |
| author_sort | Floyd Hassenrück |
| collection | DOAJ |
| description | Abstract Targeting the PI3K isoform p110δ against B cell malignancies is at the mainstay of PI3K inhibitor (PI3Ki) development. Therefore, we generated isogenic cell lines, which express wild type or mutant p110δ, for assessing the potency, isoform-selectivity and molecular interactions of various PI3Ki chemotypes. The affinity pocket mutation I777M maintains p110δ activity in the presence of idelalisib, as indicated by intracellular AKT phosphorylation, and rescues cell functions such as p110δ-dependent cell viability. Resistance owing to this substitution consistently affects the potency of p110δ-selective in contrast to most multi-targeted PI3Ki, thus distinguishing usually propeller-shaped and typically flat molecules. Accordingly, molecular dynamics simulations indicate that the I777M substitution disturbs conformational flexibility in the specificity or affinity pockets of p110δ that is necessary for binding idelalisib or ZSTK474, but not copanlisib. In summary, cell-based and molecular exploration provide comparative characterization of currently developed PI3Ki and structural insights for future PI3Ki design. |
| first_indexed | 2024-03-13T06:09:20Z |
| format | Article |
| id | doaj.art-69f0d2808dd345ce9c545e0a14f5e38c |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-13T06:09:20Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-69f0d2808dd345ce9c545e0a14f5e38c2023-06-11T11:22:49ZengNature PortfolioCommunications Biology2399-36422023-06-016111410.1038/s42003-023-04921-zFunctional impact and molecular binding modes of drugs that target the PI3K isoform p110δFloyd Hassenrück0Maria Farina-Morillas1Lars Neumann2Francesco Landini3Stuart James Blakemore4Mina Rabipour5Juan Raul Alvarez-Idaboy6Christian P. Pallasch7Michael Hallek8Rocio Rebollido-Rios9Günter Krause10University of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfFacultad de Química, Departamento de Física y Química Teórica, Universidad Nacional Autónoma de MéxicoUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfUniversity of Cologne, Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine; Center for Integrated Oncology Aachen, Bonn, Cologne, DüsseldorfAbstract Targeting the PI3K isoform p110δ against B cell malignancies is at the mainstay of PI3K inhibitor (PI3Ki) development. Therefore, we generated isogenic cell lines, which express wild type or mutant p110δ, for assessing the potency, isoform-selectivity and molecular interactions of various PI3Ki chemotypes. The affinity pocket mutation I777M maintains p110δ activity in the presence of idelalisib, as indicated by intracellular AKT phosphorylation, and rescues cell functions such as p110δ-dependent cell viability. Resistance owing to this substitution consistently affects the potency of p110δ-selective in contrast to most multi-targeted PI3Ki, thus distinguishing usually propeller-shaped and typically flat molecules. Accordingly, molecular dynamics simulations indicate that the I777M substitution disturbs conformational flexibility in the specificity or affinity pockets of p110δ that is necessary for binding idelalisib or ZSTK474, but not copanlisib. In summary, cell-based and molecular exploration provide comparative characterization of currently developed PI3Ki and structural insights for future PI3Ki design.https://doi.org/10.1038/s42003-023-04921-z |
| spellingShingle | Floyd Hassenrück Maria Farina-Morillas Lars Neumann Francesco Landini Stuart James Blakemore Mina Rabipour Juan Raul Alvarez-Idaboy Christian P. Pallasch Michael Hallek Rocio Rebollido-Rios Günter Krause Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ Communications Biology |
| title | Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ |
| title_full | Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ |
| title_fullStr | Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ |
| title_full_unstemmed | Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ |
| title_short | Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ |
| title_sort | functional impact and molecular binding modes of drugs that target the pi3k isoform p110δ |
| url | https://doi.org/10.1038/s42003-023-04921-z |
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