8ARJ
Anaplastic Lymphoma Kinase with a novel carboline inhibitor
Summary for 8ARJ
| Entry DOI | 10.2210/pdb8arj/pdb |
| Descriptor | ALK tyrosine kinase receptor, 3-(dimethylamino)-1-[3-[4-(4-methylpiperazin-1-yl)phenyl]-9~{H}-pyrido[2,3-b]indol-6-yl]prop-2-en-1-one (3 entities in total) |
| Functional Keywords | inhibitor, alk, kinase, antitumor, antitumor protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36461.89 |
| Authors | Mologni, L.,Scapozza, L.,Gambacorti-Passerini, C.,Tardy, S.,Goekjian, P.,Robinson, C.,Brown, D. (deposition date: 2022-08-17, release date: 2022-09-14, Last modification date: 2024-01-31) |
| Primary citation | Mologni, L.,Tardy, S.,Zambon, A.,Orsato, A.,Bisson, W.H.,Ceccon, M.,Viltadi, M.,D'Attoma, J.,Pannilunghi, S.,Vece, V.,Bertho, J.,Goekjian, P.,Scapozza, L.,Gambacorti-Passerini, C. Discovery of Novel alpha-Carboline Inhibitors of the Anaplastic Lymphoma Kinase. Acs Omega, 7:17083-17097, 2022 Cited by PubMed 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 showed selective inhibition of native and mutant drug-refractory ALK kinase as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a :ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150. PubMed: 35647450DOI: 10.1021/acsomega.2c00507 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.645 Å) |
Structure validation
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