5KZ0
Structure of Human Anaplastic Lymphoma Kinase in Complex With 2-[(1R)-1-{[2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]oxy}ethyl]-4-fluoro-N,N-dimethylbenzamide
Summary for 5KZ0
| Entry DOI | 10.2210/pdb5kz0/pdb |
| Related | 4cli |
| Descriptor | ALK tyrosine kinase receptor, 2-[(1~{R})-1-[2-azanyl-5-(1,3-dimethylpyrazol-4-yl)pyridin-3-yl]oxyethyl]-4-fluoranyl-~{N},~{N}-dimethyl-benzamide (3 entities in total) |
| Functional Keywords | kinase, 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 | 37306.80 |
| Authors | McTigue, M.,Deng, Y.L.,Liu, W.,Brooun, A. (deposition date: 2016-07-22, release date: 2016-08-17, Last modification date: 2023-10-04) |
| Primary citation | Johnson, T.W.,Richardson, P.F.,Bailey, S.,Brooun, A.,Burke, B.J.,Collins, M.R.,Cui, J.J.,Deal, J.G.,Deng, Y.L.,Dinh, D.,Engstrom, L.D.,He, M.,Hoffman, J.,Hoffman, R.L.,Huang, Q.,Kania, R.S.,Kath, J.C.,Lam, H.,Lam, J.L.,Le, P.T.,Lingardo, L.,Liu, W.,McTigue, M.,Palmer, C.L.,Sach, N.W.,Smeal, T.,Smith, G.L.,Stewart, A.E.,Timofeevski, S.,Zhu, H.,Zhu, J.,Zou, H.Y.,Edwards, M.P. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J. Med. Chem., 57:4720-4744, 2014 Cited by PubMed Abstract: Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity. PubMed: 24819116DOI: 10.1021/jm500261q PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
Download full validation report
