4ccb
Structure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amineStructure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine
Structural highlights
DiseaseALK_HUMAN Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:613014. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.[1] [2] [3] Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth. FunctionALK_HUMAN Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Publication Abstract from PubMedCrizotinib (1), an ALK receptor tyrosine kinase inhibitor approved by the FDA in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e which was potent across a broad panel of engineered ALK mutant cell lines, showed suitable pre-clinical PK and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M). The design of potent and selective inhibitors to overcome clinical ALK mutations resistant to crizotinib.,Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook A, Cui JJ, Dack KN, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman J, Hoffman RL, Shen H, Johnson P, Kania RS, Lam H, Lam JL, Le P, Li Q, Lingardo L, Liu W, West Lu M, McTigue MA, Palmer CL, Richardson PF, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Tsaparikos K, Wang H, Zhu H, Zhu J, Zou HY, Edwards M J Med Chem. 2014 Jan 16. PMID:24432909[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||