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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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
Descripción
Sumario:[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.