Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase.
Luca MologniSébastien TardyAlfonso ZambonAlexandre OrsatoWilliam H BissonMonica CecconMichela ViltadiJoseph D'AttomaSara PannilunghiVito VeceJerome BerthoPeter GoekjianLeonardo ScapozzaCarlo Gambacorti-PasseriniPublished in: ACS omega (2022)
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.
Keyphrases
- drug resistant
- advanced non small cell lung cancer
- diffuse large b cell lymphoma
- multidrug resistant
- protein kinase
- acinetobacter baumannii
- tyrosine kinase
- induced apoptosis
- endothelial cells
- epidermal growth factor receptor
- small molecule
- high throughput
- pseudomonas aeruginosa
- wild type
- endoplasmic reticulum stress
- cell death
- adverse drug
- electronic health record
- amino acid