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.
Mologni, L., Tardy, S., Zambon, A., Orsato, A., Bisson, W., Ceccon, M., et al. (2022). Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase. ACS OMEGA, 7(20), 17083-17097 [10.1021/acsomega.2c00507].
Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase
Mologni, Luca
Primo
;Orsato, Alexandre;Ceccon, Monica;Viltadi, Michela;Vece, Vito;Gambacorti-Passerini, CarloUltimo
2022
Abstract
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.File | Dimensione | Formato | |
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