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Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase
[Image: see text] The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug...
| Autores principales: | , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical Society
2022
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134258/ https://www.ncbi.nlm.nih.gov/pubmed/35647450 http://dx.doi.org/10.1021/acsomega.2c00507 |
| _version_ | 1784713755652784128 |
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| author | Mologni, Luca Tardy, Sébastien Zambon, Alfonso Orsato, Alexandre Bisson, William H. Ceccon, Monica Viltadi, Michela D’Attoma, Joseph Pannilunghi, Sara Vece, Vito Bertho, Jerome Goekjian, Peter Scapozza, Leonardo Gambacorti-Passerini, Carlo |
| author_facet | Mologni, Luca Tardy, Sébastien Zambon, Alfonso Orsato, Alexandre Bisson, William H. Ceccon, Monica Viltadi, Michela D’Attoma, Joseph Pannilunghi, Sara Vece, Vito Bertho, Jerome Goekjian, Peter Scapozza, Leonardo Gambacorti-Passerini, Carlo |
| author_sort | Mologni, Luca |
| collection | PubMed |
| description | [Image: see text] The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors. Several lead compounds endowed with submicromolar potency were identified. Compound 149 showed selective inhibition of native and mutant drug-refractory ALK kinase in vitro as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a 149:ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150. |
| format | Online Article Text |
| id | pubmed-9134258 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2022 |
| publisher | American Chemical Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-91342582022-05-27 Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase Mologni, Luca Tardy, Sébastien Zambon, Alfonso Orsato, Alexandre Bisson, William H. Ceccon, Monica Viltadi, Michela D’Attoma, Joseph Pannilunghi, Sara Vece, Vito Bertho, Jerome Goekjian, Peter Scapozza, Leonardo Gambacorti-Passerini, Carlo ACS Omega [Image: see text] The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors. Several lead compounds endowed with submicromolar potency were identified. Compound 149 showed selective inhibition of native and mutant drug-refractory ALK kinase in vitro as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a 149:ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150. American Chemical Society 2022-05-11 /pmc/articles/PMC9134258/ /pubmed/35647450 http://dx.doi.org/10.1021/acsomega.2c00507 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| spellingShingle | Mologni, Luca Tardy, Sébastien Zambon, Alfonso Orsato, Alexandre Bisson, William H. Ceccon, Monica Viltadi, Michela D’Attoma, Joseph Pannilunghi, Sara Vece, Vito Bertho, Jerome Goekjian, Peter Scapozza, Leonardo Gambacorti-Passerini, Carlo Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase |
| title | Discovery of Novel α-Carboline Inhibitors
of the Anaplastic Lymphoma Kinase |
| title_full | Discovery of Novel α-Carboline Inhibitors
of the Anaplastic Lymphoma Kinase |
| title_fullStr | Discovery of Novel α-Carboline Inhibitors
of the Anaplastic Lymphoma Kinase |
| title_full_unstemmed | Discovery of Novel α-Carboline Inhibitors
of the Anaplastic Lymphoma Kinase |
| title_short | Discovery of Novel α-Carboline Inhibitors
of the Anaplastic Lymphoma Kinase |
| title_sort | discovery of novel α-carboline inhibitors
of the anaplastic lymphoma kinase |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134258/ https://www.ncbi.nlm.nih.gov/pubmed/35647450 http://dx.doi.org/10.1021/acsomega.2c00507 |
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