4Z55
Anaplastic lymphoma kinase catalytic domain complexed with pyrazolopyrimidine derivative of LDK378
Summary for 4Z55
| Entry DOI | 10.2210/pdb4z55/pdb |
| Related | 3L9P 3LCS 3LCT 4MKC |
| Descriptor | ALK tyrosine kinase receptor, GLYCEROL, N~6~-[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N~4~-[2-(propan-2-ylsulfonyl)phenyl]-2H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, ... (4 entities in total) |
| Functional Keywords | catalytic domain, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cell membrane ; Single-pass type I membrane protein : Q9UM73 |
| Total number of polymer chains | 1 |
| Total formula weight | 38999.80 |
| Authors | Lee, C.C.,Spraggon, G. (deposition date: 2015-04-02, release date: 2016-02-03, Last modification date: 2024-03-06) |
| Primary citation | Michellys, P.Y.,Chen, B.,Jiang, T.,Jin, Y.,Lu, W.,Marsilje, T.H.,Pei, W.,Uno, T.,Zhu, X.,Wu, B.,Nguyen, T.N.,Bursulaya, B.,Lee, C.,Li, N.,Kim, S.,Tuntland, T.,Liu, B.,Sun, F.,Steffy, A.,Hood, T. Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors. Bioorg.Med.Chem.Lett., 26:1090-1096, 2016 Cited by PubMed Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described. PubMed: 26750252DOI: 10.1016/j.bmcl.2015.11.049 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
Download full validation report
