Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase
Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal gr...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2017.1376666 |
| _version_ | 1818334214648496128 |
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| author | Sonali Kurup Bradley McAllister Pavlina Liskova Trusha Mistry Anthony Fanizza Dan Stanford Jolanta Slawska Ulrich Keller Alexander Hoellein |
| author_facet | Sonali Kurup Bradley McAllister Pavlina Liskova Trusha Mistry Anthony Fanizza Dan Stanford Jolanta Slawska Ulrich Keller Alexander Hoellein |
| author_sort | Sonali Kurup |
| collection | DOAJ |
| description | Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1–18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1–18 allow for a structure–activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4-methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition. |
| first_indexed | 2024-12-13T14:03:59Z |
| format | Article |
| id | doaj.art-b3467f7afdca4bd8a9c2e7c1bf2bc9ed |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-13T14:03:59Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-b3467f7afdca4bd8a9c2e7c1bf2bc9ed2022-12-21T23:42:39ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742018-01-01331748410.1080/14756366.2017.13766661376666Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinaseSonali Kurup0Bradley McAllister1Pavlina Liskova2Trusha Mistry3Anthony Fanizza4Dan Stanford5Jolanta Slawska6Ulrich Keller7Alexander Hoellein8Roosevelt UniversityRoosevelt UniversityRoosevelt UniversityRoosevelt UniversityHarper CollegeHarper CollegeTechnische Universität MünchenTechnische Universität MünchenTechnische Universität MünchenSimultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1–18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1–18 allow for a structure–activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4-methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition.http://dx.doi.org/10.1080/14756366.2017.1376666Pyrrolo[2,3-d]pyrimidinesaurora kinase inhibitorsepidermal growth factor receptor kinase inhibitors |
| spellingShingle | Sonali Kurup Bradley McAllister Pavlina Liskova Trusha Mistry Anthony Fanizza Dan Stanford Jolanta Slawska Ulrich Keller Alexander Hoellein Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase Journal of Enzyme Inhibition and Medicinal Chemistry Pyrrolo[2,3-d]pyrimidines aurora kinase inhibitors epidermal growth factor receptor kinase inhibitors |
| title | Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase |
| title_full | Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase |
| title_fullStr | Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase |
| title_full_unstemmed | Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase |
| title_short | Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase |
| title_sort | design synthesis and biological activity of n4 phenylsubstituted 7h pyrrolo 2 3 d pyrimidin 4 amines as dual inhibitors of aurora kinase a and epidermal growth factor receptor kinase |
| topic | Pyrrolo[2,3-d]pyrimidines aurora kinase inhibitors epidermal growth factor receptor kinase inhibitors |
| url | http://dx.doi.org/10.1080/14756366.2017.1376666 |
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